Pyrrolidine triple reuptake inhibitors

ABSTRACT

In various embodiments, the present invention provides cycloalkyl pyrrolidine compounds and methods for their use in the treatment and/or prevention of various diseases, conditions and syndromes, including central nervous system (CNS) disorders, such as depression, anxiety, schizophrenia and sleep disorder as well as methods for their synthesis. The invention also relates to pharmaceutical compositions containing the compounds of the invention, as well as methods of inhibiting reuptake of endogenous monoamines, such as dopamine, serotonin and norepinephrine from the synaptic cleft and methods of modulating one or more monoamine transporter.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 61/151,167, filed on Feb. 9, 2009, the disclosure of which isincorporated herein by reference in its entirety for all purposes.

FIELD OF THE INVENTION

In various embodiments, the invention relates to compounds andcompositions for the treatment of central nervous system (CNS)disorders.

BACKGROUND OF THE INVENTION

Psychiatric disorders are pathological conditions of the braincharacterized by identifiable symptoms that result in abnormalities incognition, emotion, mood, or affect. These disorders may vary inseverity of symptoms, duration, and functional impairment. Psychiatricdisorders afflict millions of people worldwide resulting in tremendoushuman suffering and economic burden due to lost productivity anddependent care.

Over the past several decades, the use of pharmacological agents totreat psychiatric disorders has greatly increased, largely due toresearch advances in both neuroscience and molecular biology. Inaddition, chemists have become increasingly sophisticated at creatingchemical compounds that are more effective therapeutic agents with fewerside effects, targeted to correct the biochemical alterations thataccompany mental disorders.

Yet, despite the many advances that have occurred, many psychiatricdiseases remain untreated or inadequately treated with currentpharmaceutical agents. In addition, many of the current agents interactwith molecular targets not involved with the psychiatric disease. Thisindiscriminate binding can result in side effects that can greatlyinfluence the overall outcome of therapy. In some cases the side effectsare so severe that discontinuation of therapy is required.

Depression is an affective disorder, the pathogenesis of which cannot beexplained by any single cause or theory. It is characterized by apersistently low mood or diminished interests in one's surroundings,accompanied by at least one of the following symptoms: reduced energyand motivation, difficulty concentrating, altered sleep and appetite,and at times, suicidal ideation (American Psychiatric Association:Diagnostic and Statistical Manual of Mental Disorders, ed. 4.Washington, American Psychiatric Association, 1994). Major depression isassociated with high rates of morbidity and mortality, with suiciderates of 10-25% (Kaplan H I, Sadock B J (eds): Synopsis of Psychiatry.Baltimore, Williams & Wilkins, 1998, p. 866). The compounds of theinvention may also be used to reduce fatigue commonly associated withdepression (see, for example, “Bupropion augmentation in the treatmentof chronic fatigue syndrome with coexistent major depression episode”Schonfeldt-Lecuona et al., Pharmacopsychiatry 39(4):152-4, 2006;“Dysthymia: clinical picture, extent of overlap with chronic fatiguesyndrome, neuropharmacological considerations, and new therapeuticvistas” Brunello et al., J. Affect. Disord. 52(1-3):275-90, 1999;“Chronic fatigue syndrome and seasonal affective disorder: comorbidity,diagnostic overlap, and implications for treatment” Terman et al., Am.J. Med. 105(3A):115S-124S, 1998.).

Depression is believed to result from dysfunction in the noradrenergicor serotonergic systems, more specifically, from a deficiency of certainneurotransmitters (NTs) at functionally important adrenergic orserotonergic receptors.

Neurotransmitters produce their effects as a consequence of interactionswith specific receptors. Neurotransmitters, including norepinephrine(NE) and/or serotonin (5-hydroxytryptamine, or 5-HT), are synthesized inbrain neurons and stored in vesicles. Upon a nerve impulse, NTs arereleased into the synaptic cleft, where they interact with variouspostsynaptic receptors. Regional deficiencies in the synaptic levels of5-HT and/or NE are believed to be involved in the etiology ofdepression, wakefulness, and attention.

Norepinephrine is involved in regulating arousal, dreaming, and moods.Norepinephrine can also contribute to the regulation of blood pressure,by constricting blood vessels and increasing heart rate.

Serotonin (5-HT) is implicated in the etiology or treatment of variousdisorders. The most widely studied effects of 5-HT are those on the CNS.The functions of 5-HT are numerous and include control of appetite,sleep, memory and learning, temperature regulation, mood, behavior(including sexual and hallucinogenic behavior), cardiovascular function,smooth muscle contraction, and endocrine regulation. Peripherally, 5-HTappears to play a major role in platelet homeostasis and motility of theGI tract. The actions of 5-HT are terminated by three major mechanisms:diffusion; metabolism; and reuptake. The major mechanism by which theaction of 5-HT is terminated is by reuptake through presynapticmembranes. After 5-HT acts on its various postsynaptic receptors, it isremoved from the synaptic cleft back into the nerve terminal through anuptake mechanism involving a specific membrane transporter in a mannersimilar to that of other biogenic amines. Agents that selectivelyinhibit this uptake increase the concentration of 5-HT at thepostsynaptic receptors and have been found to be useful in treatingvarious psychiatric disorders, particularly depression.

Approaches to the treatment of depression over the years have involvedthe use of agents that increase the levels of NE and 5-HT, either byinhibiting their metabolism (e.g., monoamine oxidase inhibitors) orreuptake (e.g., tricyclic antidepressants or selective serotoninreuptake inhibitors (SSRIs)).

There are more than twenty approved antidepressant drugs available inthe United States. The classical tricyclic antidepressants (TCAs)currently available block primarily the uptake of NE and also, tovarying degrees, the uptake of 5-HT, depending on whether they aresecondary or tertiary amines. Tertiary amines such as imipramine andamitriptyline are more selective inhibitors of the uptake of 5-HT thanof catecholamines, compared with secondary amines such as desipramine.

Selective serotonin reuptake inhibitors have been investigated aspotential antidepressants. Fluoxetine (PROZAC®), sertraline (ZOLOFT),and paroxetine (PAXIL®) are three examples of SSRIs currently on theU.S. market. These agents do not appear to possess greater efficacy thanthe TCAs, nor do they generally possess a faster onset of action;however, they do have the advantage of causing less side-effects. Ofthese three SSRIs, paroxetine is the most potent inhibitor of 5-HTuptake, fluoxetine the least. Sertaline is the most selective for 5-HTversus NE uptake, fluoxetine the least selective. Fluoxetine andsertraline produce active metabolites, while paroxetine is metabolizedto inactive metabolites. The SSRIs, in general, affect only the uptakeof serotonin and display little or no affinity for various receptorsystems including muscarinic, adrenergic, dopamine, and histaminereceptors.

In addition to treating depression, several other potential therapeuticapplications for SSRIs have been investigated. They include treatment ofAlzheimer's disease, aggressive behavior, premenstrual syndrome,diabetic neuropathy, chronic pain, fibromyalgia, and alcohol abuse. Forexample, fluoxetine is approved for the treatment ofobsessive-compulsive disorder (OCD). Of particular significance is theobservation that 5-HT reduces food consumption by increasingmeal-induced satiety and reducing hunger, without producing thebehavioral effects of abuse liability associated with amphetamine-likedrugs. Thus, there is interest in the use of SSRIs in the treatment ofobesity.

Venlafaxine (EFFEXOR®) is a dual-reuptake antidepressant that differsfrom the classical TCAs and the SSRIs chemically and pharmacologicallyin that it acts as a potent inhibitor of both 5-HT and NE uptake.Neither venlafaxine nor its major metabolite has a significant affinityfor adrenergic alpha-1 receptors. Venlafaxine possesses an efficacyequivalent to that of the TCAs, and a benign side effect profile similarto those of the SSRIs.

Dopamine is hypothesized to play a major role in psychosis and certainneurodegenerative diseases, such as Parkinson's disease, where adeficiency in dopaminergic neurons is believed to be the underlyingpathology. Dopamine affects brain processes that control movement,emotional response, and ability to experience pleasure and pain.Regulation of DA plays a crucial role in our mental and physical health.Certain drugs increase DA concentrations by preventing DA reuptake,leaving more DA in the synapse. An example is methylphenidate(RITALIN®), used therapeutically to treat childhood hyperkinesias andsymptoms of schizophrenia. Dopamine abnormalities are believed tounderlie some of the core attentional abnormalities seen in acuteschizophrenics.

A therapeutic lag is associated with the use of these drugs. Patientsmust take a drug for at least three (3) weeks before achievingclinically meaningful symptom relief. Furthermore, a significant numberof patients do not respond to current therapies at all. For example, itis currently estimated that up to thirty percent (30%) of clinicallydiagnosed cases of depression are resistant to all forms of drugtherapy.

SUMMARY OF THE INVENTION

In various embodiments, the present invention relates to novelcycloalkylamines and salts thereof. It further relates to novelpharmaceutical compositions, and their use in the treatment of CNS andother disorders, e.g., depression (e.g., major depressive disorder,bipolar disorder), fibromyalgia, pain (e.g., neuropathic pain), sleepapnea, attention deficit disorder (ADD), attention deficit hyperactivitydisorder (ADHD), restless leg syndrome, schizophrenia, anxiety,obsessive compulsive disorder, posttraumatic stress disorder, seasonalaffective disorder (SAD), premenstrual dysphoria as well asneurodegenerative disease (e.g., Parkinson's disease, Alzheimer'sdisease) and seizures.

Exemplary compounds of the invention have a structure according toFormula (I):

In Formula I, the symbol R¹ represents H, C₁-C₃ substituted orunsubstituted alkyl or C₁-C₃ substituted or unsubstituted heteroalkyl.The symbols R² and R^(2a) independently represent H, C₁-C₃ substitutedor unsubstituted alkyl, C₁-C₃ substituted or unsubstituted heteroalkyl,or OR³. R³ is selected from H, C₁-C₃ substituted or unsubstituted alkyland C₁-C₃ substituted or unsubstituted heteroalkyl. Ar is an aryl group.Exemplary of Ar groups of use in the compound of the invention aresubstituted or unsubstituted naphthyl and substituted or unsubstitutedphenyl. The symbol X represents:

—CH₂—; —CH₂CH₂—; or —CH₂ZCH₂—

wherein Z is a member selected from:

and O.

R⁴ and R⁵ independently represent H, C₁-C₃ substituted or unsubstitutedalkyl, C₁-C₃ substituted or unsubstituted heteroalkyl, or OR⁶. R⁶ is H,C₁-C₃ substituted or unsubstituted alkyl or C₁-C₃ substituted orunsubstituted heteroalkyl.

Any salt, solvate, enantiomer, diastereomer, racemic mixture,enantiomerically enriched mixture, and enantiomerically pure form of theabove described compounds falls within the scope of the invention. In anexemplary embodiment, the invention provides a pharmaceuticallyacceptable salt, solvate, enantiomer, diastereomer, racemic mixture,enantiomerically enriched mixture, or enantiomerically pure form of acompound according to Formula I.

In an exemplary embodiment, the invention provides a pharmaceuticalcomposition including a compound of the invention (or a pharmaceuticallyacceptable salt, solvate, etc.) thereof, and a pharmaceuticallyacceptable carrier.

The invention also provides method of using the compounds according toFormula I. For example, the invention provides a method of inhibitingbinding of a monoamine transporter ligand to a monoamine transporter,such as serotonin transporter, dopamine transporter and norepinephrinetransporter. An exemplary method includes contacting the monoaminetransporter and a compound of the invention. In an exemplary embodimentthe monoamine transporter ligand is a monoamine, such as serotonin,dopamine and norepinephrine.

In various embodiments, the invention provides a method of inhibitingthe activity of at least one monoamine transporter, such as serotonintransporter, dopamine transporter and norepinephrine transporter.Exemplary methods include contacting the monoamine transporter and acompound of the invention.

Furthermore, in an exemplary embodiment, the invention provides a methodof inhibiting uptake of at least one monoamine, such as serotonin,dopamine and norepinephrine, by a cell. An exemplary method includescontacting the cell with a compound of the invention. In an exemplaryembodiment, the cell is a brain cell, such as a neuronal cell or a glialcell.

In various embodiments, the invention provides a method of treatingdepression by inhibiting the activity at least one monoaminetransporter. The method includes administering to a mammalian subject acompound of the invention. Exemplary compound of the invention inhibitthe activity of at least two different monoamine transporters. In anexemplary embodiment, the mammalian subject is a human.

The invention also provides a method of treating a central nervoussystem disorder. The method includes administering to a subject in needthereof a therapeutically effective amount of a compound of theinvention or a pharmaceutically acceptable salt or solvate thereof. Inan exemplary embodiment, the subject is a human.

Other embodiments, objects and advantages of the present invention areset forth in the detailed description below.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain, or cyclichydrocarbon radical, or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include di- and multivalentradicals, having the number of carbon atoms designated (i.e. C₁-C₁₀means one to ten carbons). Examples of saturated hydrocarbon radicalsinclude, but are not limited to, groups such as methyl, ethyl, n-propyl,isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl,(cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, forexample, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Anunsaturated alkyl group is one having one or more double bonds or triplebonds. Examples of unsaturated alkyl groups include, but are not limitedto, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl,3-butynyl, and the higher homologs and isomers. The term “alkyl,” unlessotherwise noted, optionally includes those derivatives of alkyl definedin more detail below, such as “heteroalkyl.” Alkyl groups that arelimited to hydrocarbon groups are termed “homoalkyl”.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane, as exemplified, but notlimited, by —CH₂CH₂CH₂CH₂—, and further includes those groups describedbelow as “heteroalkylene.” Typically, an alkyl (or alkylene) group willhave from 1 to 24 carbon atoms, with those groups having 10 or fewercarbon atoms being preferred in the present invention. A “lower alkyl”or “lower alkylene” is a shorter chain alkyl or alkylene group,generally having eight or fewer carbon atoms.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon radical, or combinations thereof, consisting of thestated number of carbon atoms and at least one heteroatom selected fromthe group consisting of O, N, Si and S, and wherein the nitrogen andsulfur atoms may optionally be oxidized and the nitrogen heteroatom mayoptionally be quaternized. The heteroatom(s) O, N and S and Si may beplaced at any interior position of the heteroalkyl group or at theposition at which the alkyl group is attached to the remainder of themolecule. Examples include, but are not limited to, —CH₂—CH₂—O—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂,—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃,and —CH═CH—N(CH₃)—CH₃. Up to two heteroatoms may be consecutive, suchas, for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃. Similarly, the term“heteroalkylene” by itself or as part of another substituent means adivalent radical derived from heteroalkyl, as exemplified, but notlimited by, —CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. Forheteroalkylene groups, heteroatoms can also occupy either or both of thechain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino,alkylenediamino, and the like). Still further, for alkylene andheteroalkylene linking groups, no orientation of the linking group isimplied by the direction in which the formula of the linking group iswritten. For example, the formula —CO₂R′— represents both —C(O)OR′ and—OC(O)R′.

The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl”, respectively. Additionally, forheterocycloalkyl, a heteroatom can occupy the position at which theheterocycle is attached to the remainder of the molecule. Examples ofcycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples ofheterocycloalkyl include, but are not limited to,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” is mean to include, but not be limited to,trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, andthe like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, substituent that can be a single ring or multiple rings(preferably from 1 to 3 rings), which are fused together or linkedcovalently. The term “heteroaryl” refers to aryl groups (or rings) thatcontain from one to four heteroatoms selected from N, O, S, Si and B,wherein the nitrogen and sulfur atoms are optionally oxidized, and thenitrogen atom(s) are optionally quaternized. A heteroaryl group can beattached to the remainder of the molecule through a heteroatom.Non-limiting examples of aryl and heteroaryl groups include phenyl,1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl,3-pyrazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 1-isoquinolyl,5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and6-quinolyl. Substituents for each of the above noted aryl and heteroarylring systems are selected from the group of acceptable substituentsdescribed below.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) optionally includes both aryl andheteroaryl rings as defined above. Thus, the term “arylalkyl” caninclude those radicals in which an aryl group is attached to an alkylgroup (e.g., benzyl, phenethyl, pyridylmethyl and the like) includingthose alkyl groups in which a carbon atom (e.g., a methylene group) hasbeen replaced by, for example, an oxygen atom (e.g., phenoxymethyl,2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and“heteroaryl”) optionally include both substituted and unsubstitutedforms of the indicated radical. Preferred substituents for each type ofradical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) are generically referred to as “alkyl groupsubstituents,” and they can be one or more of a variety of groupsselected from, but not limited to: substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted heterocycloalkyl, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″,—NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —CN and—NO₂ in a number ranging from zero to (2m′+1), where m′ is the totalnumber of carbon atoms in such radical. R′, R″, R′″ and R″″ eachpreferably independently refer to hydrogen, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, e.g., aryl substitutedwith 1-3 halogens, substituted or unsubstituted alkyl, alkoxy orthioalkoxy groups, or arylalkyl groups. When a compound of the inventionincludes more than one R group, for example, each of the R groups isindependently selected as are each R′, R″, R′ and R″″ groups when morethan one of these groups is present. When R′ and R″ are attached to thesame nitrogen atom, they can be combined with the nitrogen atom to forma 5-, 6-, or 7-membered ring. For example, —NR′R″ is meant to include,but not be limited to, 1-pyrrolidinyl and 4-morpholinyl. From the abovediscussion of substituents, one of skill in the art will understand thatthe term “alkyl” is meant to include groups including carbon atoms boundto groups other than hydrogen groups, such as haloalkyl (e.g., —CF₃ and—CH₂CF₃) and acyl (e.g., —C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and thelike).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are generically referredto as “aryl group substituents.” The substituents are selected from, forexample: substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheterocycloalkyl, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen,—SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″,—NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —CN and—NO₂, —R′, —N3, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl,in a number ranging from zero to the total number of open valences onthe aromatic ring system; and where R′, R″, R′″ and R″″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl and substituted or unsubstituted heteroaryl. When acompound of the invention includes more than one R group, for example,each of the R groups is independently selected as are each R′, R″, R′″and R″″ groups when more than one of these groups is present.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CRR′)_(q)-U-, wherein T and U are independently —NR—, —O—,—CRR′— or a single bond, and q is an integer of from 0 to 3.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula -A-(CH₂)_(r)-D-, wherein A and D are independently —CRR′—, —O—,—NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is aninteger of from 1 to 4. One of the single bonds of the new ring soformed may optionally be replaced with a double bond. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CRR′)_(s)—X″—(CR″R′″)_(d)—, where s and d are independently integersof from 0 to 3, and X″ is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituents R, R′, R″ and R′″ are preferablyindependently selected from hydrogen or substituted or unsubstituted(C₁-C₆)alkyl.

As used herein, the term “acyl” describes a substituent containing acarbonyl residue, C(O)R. Exemplary species for R include H, halogen,substituted or unsubstituted alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, and substituted orunsubstituted heterocycloalkyl.

As used herein, the term “fused ring system” means at least two rings,wherein each ring has at least 2 atoms in common with another ring.“Fused ring systems may include aromatic as well as non aromatic rings.Examples of “fused ring systems” are naphthalenes, indoles, quinolines,chromenes and the like.

As used herein, the term “heteroatom” includes oxygen (O), nitrogen (N),sulfur (S), silicon (Si) and boron (B).

The symbol “R” is a general abbreviation that represents a substituentgroup that is selected from substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, and substituted orunsubstituted heterocycloalkyl groups.

The phrase “therapeutically effective amount” as used herein means thatamount of a compound, or composition comprising a compound of thepresent invention which is effective for producing some desiredtherapeutic effect (e.g., by inhibiting uptake of a monoamine from thesynaptic cleft of a mammal, thereby modulating the biologicalconsequences of that pathway in the treated organism) at a reasonablebenefit/risk ratio applicable to any medical treatment.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in humanbeings and animals without excessive toxicity, irritation, allergicresponse, or other problem or complication, commensurate with areasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable carrier” as used herein meansany pharmaceutically acceptable material, which may be liquid or solid.Exemplary carriers include vehicles, diluents, additives, liquid andsolid fillers, excipients, solvents, solvent encapsulating materials.Each carrier must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and not injurious to thepatient. Some non-limiting examples of materials which can serve aspharmaceutically-acceptable carriers include: (1) sugars, such aslactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) pH buffered solutions; (21)polyesters, polycarbonates and/or polyanhydrides; and (22) othernon-toxic compatible substances employed in pharmaceutical formulations.

As set forth herein, certain embodiments of the present compounds maycontain a basic functional group, e.g., amino or alkylamino, or anacidic functional group, e.g., a carboxylic- or sulfonic acid and are,thus, capable of forming pharmaceutically acceptable salts withpharmaceutically acceptable acids or bases, respectively. The term“pharmaceutically acceptable salts” in this respect, refers to therelatively non-toxic, inorganic and organic acid addition salts ofcompounds of the present invention. These salts can be prepared in situin the administration vehicle or the dosage form manufacturing process,or by separately reacting a purified compound of the invention in itsfree base form with a suitable organic or inorganic acid, and isolatingthe salt thus formed during subsequent purification. Representativesalts include the hydrobromide, hydrochloride, sulfate, sulfamate,bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate,stearate, laurate, benzoate, lactate, tosylate, citrate, maleate,ascorbate, palmitate, fumarate, succinate, tartrate, napthylate,mesylate, hydroxymaleate, phenylacetate, glutamate, glucoheptonate,salicyclate, sulfanilate, 2-acetoxybenzoate, methanesulfonate, ethanedisulfonate, oxalate, isothionate, lactobionate, and laurylsulphonatesalts and the like. When the compound of the invention includes anacidic group, appropriate salts are formed from substituted orunsubstituted alkyl, heteroalky and aryl amines. See, for example, Bergeet al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19.

The term “pharmaceutically acceptable salts” includes salts of theactive compounds which are prepared with relatively nontoxic acids orbases, depending on the particular substituents found on the compoundsdescribed herein. When compounds of the present invention containrelatively acidic functionalities, base addition salts can be obtainedby contacting the neutral form of such compounds with a sufficientamount of the desired base, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable base addition salts includesodium, potassium, calcium, ammonium, organic amino, or magnesium salt,or a similar salt. When compounds of the present invention containrelatively basic functionalities, acid addition salts can be obtained bycontacting the neutral form of such compounds with a sufficient amountof the desired acid, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable acid addition salts includethose derived from inorganic acids like hydrochloric, hydrobromic,nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like glucuronic or galactunoric acids and thelike (see, for example, Berge et al., Journal of Pharmaceutical Science,66: 1-19 (1977)). Certain specific compounds of the present inventioncontain both basic and acidic functionalities that allow the compoundsto be converted into either base or acid addition salts.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents, but otherwise the salts are equivalentto the parent form of the compound for the purposes of the presentinvention.

In addition to salt forms, the present invention provides compounds,which are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplatedby the present invention and are intended to be within the scope of thepresent invention. “Compound or a pharmaceutically acceptable salt orsolvate of a compound” intends the inclusive meaning of “or”, in that amaterial that is both a salt and a solvate is encompassed.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers and individual isomers are encompassed within thescope of the present invention. Optically active (R)- and (S)-isomersmay be prepared using chiral synthons or chiral reagents, or resolvedusing conventional techniques. When the compounds described hereincontain olefinic double bonds or other centers of geometric asymmetry,and unless specified otherwise, it is intended that the compoundsinclude both E and Z geometric isomers. Likewise, all tautomeric formsare also intended to be included.

The graphic representations of racemic, ambiscalemic and scalemic orenantiomerically pure compounds used herein are taken from Maehr, J.Chem. Ed., 62: 114-120 (1985): solid and broken wedges are used todenote the absolute configuration of a chiral element; wavy linesindicate disavowal of any stereochemical implication which the bond itrepresents could generate; solid and broken bold lines are geometricdescriptors indicating the relative configuration shown but not implyingany absolute stereochemistry; and wedge outlines and dotted or brokenlines denote enantiomerically pure compounds of indeterminate absoluteconfiguration.

As used herein, the term “enantiomerically enriched” or“diastereomerically enriched” refers to a compound having anenantiomeric excess (ee) or a diastereomeric excess (de) greater thanabout 50%, preferably greater than about 70% and more preferably greaterthan about 90%. In general, higher than about 90% enantiomeric ordiastereomeric purity is particularly preferred, e.g., thosecompositions with greater than about 95%, greater than about 97% andgreater than about 99% ee or de.

The terms “enantiomeric excess” and “diastereomeric excess” are usedinterchangeably herein. Compounds with a single stereocenter arereferred to as being present in “enantiomeric excess”, those with atleast two stereocenters are referred to as being present in“diastereomeric excess”.

For example, the term “enantiomeric excess” is well known in the art andis defined as:

${ee}_{a} = {\left( \frac{{{{conc}.\mspace{14mu} {of}}\mspace{14mu} a} - {{{conc}.\mspace{14mu} {of}}\mspace{14mu} b}}{{{{conc}.\mspace{14mu} {of}}\mspace{14mu} a} + {{{conc}.\mspace{14mu} {of}}\mspace{14mu} b}} \right) \times 100}$

The term “enantiomeric excess” is related to the older term “opticalpurity” in that both are measures of the same phenomenon. The value ofcc will be a number from 0 to 100, zero being racemic and 100 beingenantiomerically pure. A compound which in the past might have beencalled 98% optically pure is now more precisely characterized by 96% ee.A 90% ee reflects the presence of 95% of one enantiomer and 5% of theother(s) in the material in question.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areintended to be encompassed within the scope of the present invention.

The term “monoamine transporter ligand” refers to any compound, whichbinds to a monoamine transporter. Ligands include endogenous monoamines,which are the natural ligands for a given monoamine transporter as wellas drug molecules and other compounds, such as synthetic molecules knownto bind to a particular monoamine transporter. In one example, theligand includes a radioisotope, such as tritium or is otherwise (e.g.,fluorescently) labeled. It is within the abilities of a skilled personto select an appropriate ligand for a given monoamine transporter. Forexample, known ligands for the dopamine transporter include dopamine andWIN35428, known ligands for the serotonin transporter include5-hydroxytryptamine (serotonin) and citalopram, and ligands for thenorepinephrine transporter include norepinephrine and nisoxetine.

The term “central nervous system disorder” refers to any abnormalcondition of the central nervous system of a mammal. Central nervoussystem disorder includes neurodegenerative diseases such Alzheimer'sdisease and Parkinson's disease, neuropsychiatric diseases (e.g.,schizophrenia), anxieties, sleep disorders, depression, dementias,movement disorders, psychoses, alcoholism, post-traumatic stressdisorder and the like. “Central nervous system disorder” also includesany condition associated with the disorder, such as loss of memoryand/or loss of cognition. For instance, a method of treating aneurodegenerative disease would also include treating or preventing lossof neuronal function characteristic of such disease. “Central nervoussystem disorder” also includes any disease or condition that isimplicated, at least in part, in monoamine (e.g., norepinephrine)signaling pathways (e.g., cardiovascular disease).

The term “neurological disorder” refers to any condition of the centralor peripheral nervous system of a mammal. The term “neurologicaldisorder” includes neurodegenerative diseases (e.g., Alzheimer'sdisease, Parkinson's disease and amyotrophic lateral sclerosis),neuropsychiatric diseases (e.g. Schizophrenia and anxieties, such asgeneral anxiety disorder). Exemplary neurological disorders include MLS(cerebellar ataxia), Huntington's disease, Down syndrome, multi-infarctdementia, status epilecticus, contusive injuries (e.g. spinal cordinjury and head injury), viral infection induced neurodegeneration,(e.g. AIDS, encephalopathies), epilepsy, benign forgetfulness, closedhead injury, sleep disorders, depression (e.g., bipolar disorder),dementias, movement disorders, psychoses, alcoholism, post-traumaticstress disorder and the like. “Neurological disorder” also includes anycondition associated with the disorder. For instance, a method oftreating a neurodegenerative disorder includes methods of treating lossof memory and/or loss of cognition associated with a neurodegenerativedisorder. Such method would also include treating or preventing loss ofneuronal function characteristic of neurodegenerative disorder.

“Pain” is an unpleasant sensory and emotional experience. Painclassifications have been based on duration, etiology orpathophysiology, mechanism, intensity, and symptoms. The term “pain” asused herein refers to all categories of pain, including pain that isdescribed in terms of stimulus or nerve response, e.g., somatic pain(normal nerve response to a noxious stimulus) and neuropathic pain(abnormal response of a injured or altered sensory pathway, oftenwithout clear noxious input); pain that is categorized temporally, e.g.,chronic pain and acute pain; pain that is categorized in terms of itsseverity, e.g., mild, moderate, or severe; and pain that is a symptom ora result of a disease state or syndrome, e.g., inflammatory pain, cancerpain, AIDS pain, arthropathy, migraine, trigeminal neuralgia, cardiacischaemia, and diabetic neuropathy (see, e.g., Harrison's Principles ofInternal Medicine, pp. 93-98 (Wilson et al., eds., 12th ed. 1991);Williams et al., J. of Med. Chem. 42: 1481-1485 (1999), herein eachincorporated by reference in their entirety). “Pain” is also meant toinclude mixed etiology pain, dual mechanism pain, allodynia, causalgia,central pain, hyperesthesia, hyperpathia, dysesthesia, and hyperalgesia.

“Somatic” pain, as described above, refers to a normal nerve response toa noxious stimulus such as injury or illness, e.g., trauma, burn,infection, inflammation, or disease process such as cancer, and includesboth cutaneous pain (e.g., skin, muscle or joint derived) and visceralpain (e.g., organ derived).

“Neuropathic pain” is a heterogeneous group of neurological conditionsthat result from damage to the nervous system. “Neuropathic” pain, asdescribed above, refers to pain resulting from injury to or dysfunctionsof peripheral and/or central sensory pathways, and from dysfunctions ofthe nervous system, where the pain often occurs or persists without anobvious noxious input. This includes pain related to peripheralneuropathies as well as central neuropathic pain. Common types ofperipheral neuropathic pain include diabetic neuropathy (DN or DPN),post-herpetic neuralgia (PHN), and trigeminal neuralgia (TGN). Centralneuropathic pain, involving damage to the brain or spinal cord, canoccur following stroke, spinal cord injury, and as a result of multiplesclerosis.

Common clinical features of neuropathic pain include sensory loss,allodynia (non-noxious stimuli produce pain), hyperalgesia andhyperpathia (delayed perception, summation, and painful aftersensation).Pain is often a combination of nociceptive and neuropathic types, forexample, mechanical spinal pain and radiculopathy or myelopathy.

“Acute pain”, is the normal, predicted physiological response to anoxious chemical, thermal or mechanical stimulus typically associatedwith invasive procedures, trauma and disease. It is generallytime-limited, and may be viewed as an appropriate response to a stimulusthat threatens and/or produces tissue injury. “Acute pain”, as describedabove, refers to pain which is marked by short duration or sudden onset.

“Chronic pain” occurs in a wide range of disorders, for example, trauma,malignancies and chronic inflammatory diseases such as rheumatoidarthritis. Chronic pain usually lasts more than about six months. Inaddition, the intensity of chronic pain may be disproportionate to theintensity of the noxious stimulus or underlying process. “Chronic pain”,as described above, refers to pain associated with a chronic disorder,or pain that persists beyond resolution of an underlying disorder orhealing of an injury, and that is often more intense than the underlyingprocess would predict. It may be subject to frequent recurrence.

“Inflammatory pain” is pain in response to tissue injury and theresulting inflammatory process. Inflammatory pain is adaptive in that itelicits physiologic responses that promote healing. However,inflammation may also affect neuronal function. Inflammatory mediators,including PGE₂ induced by the COX2 enzyme, bradykinins, and othersubstances, bind to receptors on pain-transmitting neurons and altertheir function, increasing their excitability and thus increasing painsensation. Much chronic pain has an inflammatory component.“Inflammatory pain”, as described above, refers to pain which isproduced as a symptom or a result of inflammation or an immune systemdisorder.

“Visceral pain”, as described above, refers to pain which is located inan internal organ.

“Mixed etiology” pain, as described above, refers to pain that containsboth inflammatory and neuropathic components.

“Dual mechanism” pain, as described above, refers to pain that isamplified and maintained by both peripheral and central sensitization.

“Causalgia”, as described above, refers to a syndrome of sustainedburning, allodynia, and hyperpathia after a traumatic nerve lesion,often combined with vasomotor and sudomotor dysfunction and latertrophic changes.

“Central” pain, as described above, refers to pain initiated by aprimary lesion or dysfunction in the central nervous system.

“Hyperesthesia”, as described above, refers to increased sensitivity tostimulation, excluding the special senses.

“Hyperpathia”, as described above, refers to a painful syndromecharacterized by an abnormally painful reaction to a stimulus,especially a repetitive stimulus, as well as an increased threshold. Itmay occur with allodynia, hyperesthesia, hyperalgesia, or dysesthesia.

“Dysesthesia”, as described above, refers to an unpleasant abnormalsensation, whether spontaneous or evoked. Special cases of dysesthesiainclude hyperalgesia and allodynia,

“Hyperalgesia”, as described above, refers to an increased response to astimulus that is normally painful. It reflects increased pain onsuprathreshold stimulation.

“Allodynia”, as described above, refers to pain due to a stimulus thatdoes not normally provoke pain.

The term “convulsion” refers to a CNS disorder and is usedinterchangeably with “seizure,” although there are many types ofseizure, some of which have subtle or mild symptoms instead ofconvulsions. Seizures of all types may be caused by disorganized andsudden electrical activity in the brain. Convulsions are when a person'sbody shakes rapidly and uncontrollably. During convulsions, the person'smuscles contract and relax repeatedly. If a person has recurringseizures, and there are no underlying causes that can be identified,that person is said to have epilepsy.

The term “depression” includes all forms of depression, which includemajor depressive disorder (MDD), bipolar disorder, seasonal affectivedisorder (SAD) and dysthymia. “Major depressive disorder” is used hereininterchangeably with “unipolar depression” and “major depression.“Depression” also includes any condition commonly associated withdepression, such as all forms of fatigue (e.g., chronic fatigue syndrom)and cognitive deficits.

II. Introduction

One strategy to develop effective therapies is the use of broad spectrumcompounds (e.g., antidepressants) that simultaneously inhibit thereuptake of more than one biogenic amine, such as serotonin (5-HT),norepinephrine (NE) and dopamine (DA). The rationale for this approachis based upon clinical and preclinical evidence showing thatdeficiencies in dopaminergic function can be correlated with anhedonia,which is a core symptom of depression. Baldessarini, R. J., “Drugs andthe Treatment of Psychiatric Disorders: Depression and Mania, in Goodmanand Gilman's The Pharmacological Basis of Therapeutics 431-459 (9^(th)ed 1996) Hardman et al. eds.

An exemplary advantage of selected compounds and compositions of thepresent invention is their ability to increase synaptic availability ofat least two, or three, neurotransmitters (e.g, NE, 5-HT and DA) byinhibiting their (re)uptake from the synaptic cleft. Skolnick andcoworkers report on a body of preclinical evidence suggesting that thetherapeutic profile of an antidepressant concurrently increasing thesynaptic availability of DA, NE and 5-HT will differ from a compoundinhibiting only NE and/or 5-HT. Skolnick, P. et al.,“Antidepressant-like actions of DOV-21,947: a “triple” reuptakeinhibitor,” Eur. J. Pharm. 2003, 461, 103.

For example, Skolnick and coworkers have reported that a compound, DOV21,947 ((+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane), inhibitsthe reuptake of serotonin, norepinephrine, and dopamine in humanembryonic kidney (HEK293) cells expressing the corresponding humanrecombinant transporters (IC₅₀ values of 12, 23 and 96 nM,respectively). Skolnick, P. et al., “Antidepressant-like actions ofDOV-21,947: a “triple” reuptake inhibitor,” Eur. J. Pharm. 2003, 461,99. In addition, DOV 21,947 reduces the duration of immobility in theforced swim test (in rats) and also produces a dose-dependent reductionin immobility in the tail suspension test. Additional evidence can befound in preclinical data for new triple reuptake inhibitors such as DOV21,947 in, e.g., U.S. Pat. No. 6,372,919, wherein DOV 21,947 wasdisclosed as having a significantly greater affinity for thenorepinephrine and serotonin uptake sites than the racemic compound,(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane.

Taken together, the preclinical data for compounds such as DOV 21,947indicate that dual or triple reuptake inhibitors form the basis of noveltreatments for CNS (e.g., depression) and other disorders in the clinic

III. Compositions A. Pyrrolidine Cycloalkyl Amines

In an exemplary embodiment, the invention provides a compound having astructure according to Formula (I):

In Formula I, the symbol R¹ represents H, C₁-C₃ substituted orunsubstituted alkyl or C₁-C₃ substituted or unsubstituted heteroalkyl.The symbols R² and R^(2a) independently represent H, C₁-C₃ substitutedor unsubstituted alkyl, C₁-C₃ substituted or unsubstituted heteroalkyl,or OR³. R³ is selected from H, C₁-C₃ substituted or unsubstituted alkyland C₁-C₃ substituted or unsubstituted heteroalkyl. Ar is an aryl group,particularly a member selected from substituted or unsubstitutednaphthyl and substituted or unsubstituted phenyl. The symbol Xrepresents:

—CH₂—; —CH₂CH₂—; or —CH₂ZCH₂—

wherein Z is a member selected from:

and O.

R⁴ and R⁵ independently represent H, C₁-C₃ substituted or unsubstitutedalkyl, C₁-C₃ substituted or unsubstituted heteroalkyl, or OR⁶. R⁶ is H,C₁-C₃ substituted or unsubstituted alkyl or C₁-C₃ substituted orunsubstituted heteroalkyl.

Exemplary compounds of the invention include:

In various embodiments, Ar is a member selected from substituted orunsubstituted phenyl, and substituted or unsubstituted naphthyl. In anexemplary embodiment, Ar is a phenyl substituted with at least onehalogen, or Ar is unsubstituted naphthyl. The phenyl group can besusbstituted with any halogen moiety; however, in one embodiment, it issubstituted with at least one chloro moiety.

In an exemplary embodiment, Ar has a formula which is a member selectedfrom:

wherein X¹ and X² are independently selected from H and halogen. Inexemplary compounds of the invention, at least one of X¹ and X² ishalogen.

In certain embodiments, the invention provides compounds according toFormula I in which the moiety:

has a formula which is a member selected from:

In various exemplary embodiments, the invention provides compoundsaccording to Formula I in which the moiety:

has a formula selected from:

and Ar has a formula selected from:

In an exemplary embodiment, the invention provides compounds accordingto Formula I wherein the moiety:

has the formula:

andAr has a formula selected from:

Exemplary compounds of the invention include an amine moiety (e.g., aprimary, secondary or tertiary amino group) and as such can be convertedinto a salt form by contacting the compound (e.g., the free base) withan acid. In an exemplary embodiment, the salt form is generated toconvert an otherwise oily or viscous compound into a solid substance foreasier handling. In another exemplary embodiment, converting the freebase of a compound of the invention into a corresponding salt increasessolubility of the compound in aqueous media, which can effect biologicalcharacteristics, such as bioavailability, pharmacokinetics andpharmacodynamics. Hence, any salt forms, such as pharmaceuticallyacceptable salts, including salts of inorganic acids (e.g.,hydrochloride salts) or organic acids, of the compounds of the inventionare within the scope of the current invention. Also within the scope ofthe invention are any prodrugs of the compounds of the invention. Forexample, R³ and R⁴ can be any group, which is cleavable in vivo toresult in an amine, such as a primary or secondary amine.

B. Compositions Including Stereoisomers

The compounds of the invention can include one or more stereocenter andmay exist in particular geometric or stereoisomeric forms. Compounds canbe chiral, racemic or be present in a composition including one or morestereoisomer. The current invention encompasses any enantiomer,diastereomer, racemic mixtures, enantiomerically enriched mixtures, anddiastereomerically enriched mixture as well as any enantiomerically ordiastereomerically (essentially) pure forms of the compounds of theinvention. The invention contemplates cis- and trans-isomers, (−)- and(+)-enantiomers, (D)-isomers, (L)-isomers, as falling within the scopeof the invention. Additional asymmetric carbon atoms may be present in asubstituent such as an alkyl group. All such isomers, as well asmixtures thereof, are intended to be included in this invention.

If, for instance, a particular enantiomer of a compound of the presentinvention is desired, it may be prepared by asymmetric synthesis, or byderivatization with a chiral auxiliary, where the resultingdiastereomeric mixture is separated and the auxiliary group cleaved toprovide the pure desired enantiomers. Alternatively, where the moleculecontains a basic functional group, such as an amino group, or an acidicfunctional group, such as a carboxyl group, diastereomeric salts may beformed with an appropriate optically active acid or base, followed byresolution of the diastereomers thus formed by fractionalcrystallization or chromatographic means known in the art, andsubsequent recovery of the pure enantiomers. In addition, separation ofenantiomers and diastereomers is frequently accomplished usingchromatography employing chiral, stationary phases, optionally incombination with chemical derivatization (e.g., formation of carbamatesfrom amines).

Hence, in one embodiment, the invention provides a composition includinga first stereoisomer and at least one additional stereoisomer of acompound of the invention. The first stereoisomer may be present in adiastereomeric or enantiomeric excess of at least about 80%, preferablyat least about 90% and more preferably at least about 95%. In aparticularly preferred embodiment, the first stereoisomer is present ina diastereomeric or enantiomeric excess of at least about 96%, at leastabout 97%, at least about 98%, at least about 99% or at least about99.5%. Enantiomeric or diastereomeric excess may be determined relativeto exactly one other stereoisomer, or may be determined relative to thesum of at least two other stereoisomers. In an exemplary embodiment,enantiomeric or diastereomeric excess is determined relative to allother detectable stereoisomers, which are present in the mixture.Stereoisomers are detectable if a concentration of such stereoisomer inthe analyzed mixture can be determined using common analytical methods,such as chiral HPLC.

C. Synthesis of the Compounds 1. General

Compounds of the invention may be synthesized as a racemic mixture, amixture of cis and trans isomers, or a mixture of two or morediastereomers. Stereoisomers may be separated at an appropriatesynthetic stage, for example, by chiral column chromatography, such asHPLC to give enantiomerically/diastereomerically enriched orenantiomerically or diastereomerically pure forms of the respectivestereoisomers. Cis and trans assignments may be made on the basis of NMRcoupling patterns optionally in conjunction with literature values.Absolute configurations can be determined by synthesis from chiralprecursor of known configuration, or by X-ray crystallographicdetermination using crystallized materials.

Cis- and trans-configurations are defined according to the relativeconfiguration of the amine-bearing side chain and the substituent on thecyclalkyl ring. When more than one substituent is present, the higherorder (IUPAC) substituent is used for the determination of cis- andtrans-configuration.

Compounds of the invention may be synthesized according to the variousschemes included herein. It is within the abilities of a person skilledin the art to select appropriate alternative reagents replacing theexemplary reagents shown in the schemes in order to synthesize a desiredcompound of the invention. It is also within the abilities of a skilledartisan to omit or add synthetic steps when necessary. As a non-limitingexample, Ar in the schemes set forth herein is selected from substitutedor unsubstituted naphthyl and substituted or unsubstituted phenyl. In anexemplary embodiment, Ar is 3,4-dichlorophenyl.

2. General Synthesis of Pyrrolidinyl Cycloalkylamines

In one embodiment, the compounds of the invention are synthesized fromthe corresponding nitrile a as shown in Scheme 1, below.

In the first step, nitrite a is alkylated with a dibromo-alkyl orheteroalkyl reagent, forming the corresponding cycloalkyl nitrile b,which is reduced to aldhehyde c. The aldehyde Wittig substrate c isconverted to ester d and, subsequently to carboxylic acid-nitrile e. Thenitrile and carboxylic acid groups are reduced to the correspondingamine and alcohol moieties, respectively (f) and pyrrolidine g is formedby cyclizing this substrate. The pyrrolidine amine is protected as theN-Boc or N-Troc moiety, forming compound h, which is separated into itsenantiomers, i and j, by chiral chromatography. The enantiomers aredeprotected, forming k and l, which are optionally N-alkylated,providing n and m, respectively.

Stereoisomeric mixtures of compounds of the invention are resolved,purified or enriched in one stereoisomer using art-recogized methodsincluding, but not limited to, chiral chromatography. An exemplaryenrichment procedure using an RO1 column is set forth in Scheme 2:

Scheme 3 provides an exemplary route for the synthesis and purificationof substituted cyclohexyl compounds of the invention. Thus, protectedcyano cyclohexyl ketone a is reduced to the corresponding aldehyde b byaction of Dibal, forming the Wittig substrate, which is subsequentlyconverted to unsaturated ester c. The double bond of c is converted tothe corresponding nitrite d, and the nitrile and ester moieties arereduced to the corresponding amine and alcohol moieties, respectively,forming e. The amine moiety of e is protected as the Boc group andresulting compound f is cyclized to form pyrrolidinyl compound g. Themasked ketone of compound g is deprotected, forming h, which isconverted to substituted cyclohexyl derivative i by the action of methylmagnesium bromide. The resulting mixture of stereoisomers is resolvedusing a RO1 column. The first peak, contains pure 1, which isdeprotected by removing the Boc moiety. The second peak includes twocompounds, j and k, which are further resolved by resubmission to an RO1column, affording n and p, which are subsequently deprotected byremoving the Boc group, producing o and q, respectively. The third peakfrom the first chromatography provides pure 1, which is deprotected toform r.

In Scheme 4, an exemplary route for resolution of various stereoisomersof the invention is shown. Protected pyrrolidine ketone a is reduced totwo racemic mixtures of the corresponding cyclohexyl alcohol, which areresolved using an RO1 column to a first peak containing pure b, a secondpeak containing a mixture of d and e and a third peak containing pure h.The N-Boc moiety of the compounds in the first and third peak, b and h,respectively are cleaved providing c and i. The compounds in the secondpeak are deprotected and submitted to reverse phase chromatography,affording pure f and g.

In Scheme 5, each of a, b, c and d are O-alkylated with methyl iodideand the resulting ether is deprotected to form compounds j, k, l and m.

In Scheme 6, N—H pyrrolidone a is protected as the N-Boc derivative (b)and this compound is oxidized to the corresponding N-protected lactams cand d. The lactam is hydroxylated at a position alpha to the lactamcarbonyl moiety, forming e, which is deprotected by removal of Boc toprovide f, which is reductively decarbonylated by the action of BH₃,providing g.

In Scheme 7, cyclopentyl nitrile a is converted to the correspondingketone b, which is homologated to the corresponding methylene methylester c. Compound d is formed by conversion of the ketone carbonyl of cinto the corresponding nitrile. The stereochemical mixture of d isresolved into peaks containing e and h. The compounds from these peaksare reacted through two steps to form compounds g and h.

Table 1 sets forth exemplary compounds of the invention preparedaccording to the methods set forth herein.

TABLE 1 Exemplary Compounds Cpd No. Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

D. Pharmaceutical Compositions

The present invention also provides a pharmaceutical compositionincluding a compound of the invention (e.g., a compound of Formula (I))or a pharmaceutically acceptable salt or solvate thereof, and at leastone pharmaceutically acceptable carrier.

As described in detail below, the pharmaceutical compositions of thepresent invention may be specially formulated for administration insolid or liquid form, including those adapted for oral administration,e.g., tablets, drenches (aqueous or non-aqueous solutions orsuspensions), parenteral administration (including intravenous andintramuscular), or epidural injection as, for example, a sterilesolution or suspension, or sustained release formulation. Thepharmaceutical compositions of the present invention may also bespecifically formulated for administration transdermally.

The pharmaceutical compositions of the invention may be administeredorally, parenterally, subcutaneously, transdermally, nasally, or by analsuppository. The pharmaceutical compositions of the invention may alsobe administered using controlled delivery devices.

Formulations of the present invention include those suitable for oraland parenteral administration, particularly intramuscular, intravenousand subcutaneous administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient which canbe combined with a carrier material to produce a single dosage form willvary depending upon the host being treated and the particular mode ofadministration. The amount of active ingredient which can be combinedwith a carrier material to produce a single dosage form will generallybe that amount of the compound which produces a therapeutic effect,without being toxic to the patient. Generally, out of one hundredpercent, this amount will range from about 1 percent to aboutninety-nine percent of active ingredient.

In certain embodiments, a formulation of the present invention comprisesan excipient selected from the group consisting of cyclodextrins,liposomes, micelle forming agents, e.g., bile acids, and polymericcarriers, e.g., polyesters and polyanhydrides; and a compound of thepresent invention. In certain embodiments, an aforementioned formulationrenders orally bioavailable a compound of the present invention.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, caplets, lozenges (usinga flavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia), each containing a predeterminedamount of a compound of the present invention as an active ingredient. Acompound of the present invention may also be administered as a bolus,electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, caplets, pills, dragees, powders, granules and thelike), the active ingredient is mixed with one or more pharmaceuticallyacceptable carriers, such as sodium citrate or dicalcium phosphate,and/or any of the following: (1) fillers or extenders, such as starches,lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders,such as, for example, carboxymethylcellulose, alginates, gelatin,polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such asglycerol; (4) disintegrating agents, such as agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and sodium carbonate; (5) solution retarding agents, such as paraffin;(6) absorption accelerators, such as quaternary ammonium compounds; (7)wetting agents, such as, for example, cetyl alcohol, glycerolmonostearate, and non-ionic surfactants; (8) absorbents, such as kaolinand bentonite clay; (9) lubricants, such a talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof; and (10) coloring agents. In the case of capsules,tablets and pills, the pharmaceutical compositions may also comprisebuffering agents. Solid compositions of a similar type may also beemployed as fillers in soft and hard-shelled gelatin capsules using suchexcipients as lactose or milk sugars, as well as high molecular weightpolyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be formulated for rapid release,e.g., freeze-dried. They may be sterilized by, for example, filtrationthrough a bacteria-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedin sterile water, or some other sterile injectable medium immediatelybefore use. These compositions may also optionally contain opacifyingagents and may be of a composition that they release the activeingredient(s) only, or preferentially, in a certain portion of thegastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active ingredient can also be in micro-encapsulated form,if appropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluents commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically-acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containsugars, alcohols, antioxidants, buffers, bacteriostats, solutes whichrender the formulation isotonic with the blood of the intended recipientor suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms upon the subject compounds may be ensuredby the inclusion of various antibacterial and antifungal agents, forexample, paraben, chlorobutanol, phenol sorbic acid, and the like. Itmay also be desirable to include isotonic agents, such as sugars, sodiumchloride, and the like into the compositions. In addition, prolongedabsorption of the injectable pharmaceutical form may be brought about bythe inclusion of agents which delay absorption such as aluminummonostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissue. Pharmaceuticalcompositions or unit dosage forms of the present invention in the formof prolonged-action tablets may comprise compressed tablets formulatedto release the drug substance in a manner to provide medication over aperiod of time. There are a number of tablet types that includedelayed-action tablets in which the release of the drug substance isprevented for an interval of time after administration or until certainphysiological conditions exist. Repeat action tablets may be formed thatperiodically release a complete dose of the drug substance to thegastrointestinal fluids. Also, extended release tablets thatcontinuously release increments of the contained drug substance to thegastrointestinal fluids may be formed.

Compounds of the invention can be also administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the compounds of this invention. The invention thus encompassessingle unit dosage forms suitable for oral administration such as, butnot limited to, tablets, capsules, gelcaps, and caplets that are adaptedfor controlled-release.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased patient compliance. In addition,controlled-release formulations can be used to affect the time of onsetof action or other characteristics, such as blood levels of the drug,and can thus affect the occurrence of side (e.g., adverse) effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release other amountsof drug to maintain this level of therapeutic or prophylactic effectover an extended period of time. In order to maintain this constantlevel of drug in the body, the drug must be released from the dosageform at a rate that will replace the amount of drug being metabolizedand excreted from the body. Controlled-release of an active ingredientcan be stimulated by various conditions including, but not limited to,pH, temperature, enzymes, water, or other physiological conditions orcompounds.

Compounds of the present invention may also be formulated astransdermal, topical, and mucosal dosage forms, which forms include, butare not limited to, ophthalmic solutions, sprays, aerosols, creams,lotions, ointments, gels, solutions, emulsions, suspensions, or otherforms known to one of skill in the art. See, e.g., Remington'sPharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa.(1980 & 1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed.,Lea & Febiger, Philadelphia (1985). Transdermal dosage forms include“reservoir type” or “matrix type” patches, which can be applied to theskin and worn for a specific period of time to permit the penetration ofa desired amount of active ingredients.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide transdermal, topical, and mucosal dosageforms encompassed by this invention are well known to those skilled inthe pharmaceutical arts, and depend on the particular tissue to which agiven pharmaceutical composition or dosage form will be applied.

Depending on the specific tissue to be treated, additional componentsmay be used prior to, in conjunction with, or subsequent to treatmentwith active ingredients of the invention. For example, penetrationenhancers can be used to assist in delivering the active ingredients tothe tissue.

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, mayalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

When the compounds of the present invention are administered aspharmaceuticals, to humans and animals, they can be given per se or as apharmaceutical composition containing, for example, 0.1 to 99.5% ofactive ingredient in combination with a pharmaceutically acceptablecarrier.

The preparations of the present invention may be given orally andparenterally. They are of course given in forms suitable for eachadministration route. For example, they are administered in tablets orcapsule form, by injection, and by intravenous administration. In oneembodiment, oral administrations are preferred.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular,subarachnoid, intraspinal and intrastemal injection and infusion.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion ormetabolism of the particular compound being employed, the duration ofthe treatment, other drugs, compounds and/or materials used incombination with the particular compound employed, the age, sex, weight,condition, general health and prior medical history of the patient beingtreated, and like factors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

The present invention also provides a unit dosage form of a compound ofthe invention. In general, the unit dosage form includes the compoundand a pharmaceutically acceptable carrier, diluent, excipient, etc. suchas those set forth herein or otherwise known in the art. In an exemplaryembodiment, the unit dosage formulation includes from about 0.1 to about7000 mg of a compound of the invention. In various embodiments, the unitdosage formulation includes from 2.5 mg to about 500 mg, or from about 5mg to about 50 mg of a compound of the invention. In variousembodiments, the unit dosage includes a dose sufficient to provideantidepressant activity in the subject to whom the unit dosageformulation is administered. In various embodiments, the unit dosageprovides sufficient active compound to provide anti-depressant activityin the subject to whom it is administered when the unit dosage is orallyadministered.

IV. Methods A. General

The present invention also provides methods of using the compounds ofthe invention, which are set forth in greater detail hereinbelow. Theterms “treatment” or “treating” is intended to encompass therapy,preventing (prophylaxis), preventing relapse, and amelioration of acutesymptoms. Note that “treating” refers to either or both of theamelioration of symptoms and the resolution of the underlying condition.In many of the conditions of the invention, the administration of acompound or composition of the invention may act not directly on thedisease state, but rather on some pernicious symptom, and theimprovement of that symptom leads to a general and desirableamelioration of the disease state

The patient receiving this treatment is any animal in need, includingprimates, in particular humans, and other mammals such as equines,cattle, swine and sheep, as well as poultry and pets in general.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound which is the lowest dose effective toproduce a therapeutic effect. Such an effective dose will generallydepend upon the factors described above. Generally, intravenous,intracerebroventricular and subcutaneous doses of the compounds of thisinvention for a patient will range from about 0.005 mg per kilogram toabout 5 mg per kilogram of body weight per day.

The compounds and pharmaceutical compositions of the invention can beadministered in conjunction with other pharmaceutical agents, forinstance antimicrobial agents, such as penicillins, cephalosporins,aminoglycosides and glycopeptides, and other psychoactive agents.Conjunctive therapy thus includes sequential, simultaneous and separateadministration of the active compound in a way that the therapeuticeffects of the first administered agent have not entirely disappearedwhen the subsequent agent is administered.

B. Binding to Monoamine Transporter

In another aspect the invention provides a method of binding a compoundof the invention to a monoamine transporter. The method includescontacting the monoamine transporter and a compound of the invention.

In yet another aspect, the invention provides a method of inhibitingbinding of a monoamine transporter ligand to a monoamine transporter(such as serotonin transporter, dopamine transporter and norepinephrinetransporter). The method includes contacting the monoamine transporterand a compound of the invention. In an exemplary embodiment themonoamine transporter ligand is an endogenous monoamine, such asserotonin, dopamine or norepinephrine. In another exemplary embodiment,the ligand is a drug molecule or another small molecule known to havebinding affinity to a monoamine transporter. In another exemplaryembodiment, the monoamine transporter ligand is a radioactively labeledcompound, known to bind to the monoamine transporter.

In an exemplary embodiment, inhibition of ligand binding is shown usingan ex vivo binding assay, such as those described herein, below inExample 7. In an exemplary embodiment, the compound of the inventioninhibits mean binding by between about 1% and about 100%, preferably bybetween about 10% and about 100%, more preferably by between about 20%and about 90% when compared to vehicle Inhibition of mean binding ispreferably dose dependent.

C. Inhibition of Monoamine Transporter Activity

In yet another aspect, the invention provides a method of modulating(e.g, inhibiting, augmenting) the activity of at least one monoaminetransporter, such as serotonin transporter, dopamine transporter andnorepinephrine transporter. The method includes contacting the monoaminetransporter and a compound of the invention. In an exemplary embodiment,the monoamine transporter is contacted with a compound of the inventionby administering to a subject a therapeutically effective amount of thecompound of the invention, e.g., a compound according to Formula (I), ora pharmaceutically acceptable salt or solvate thereof. In a preferredembodiment, the subject is a human. In another exemplary embodiment, themonoamine transporter is dopamine transporter (DAT), serotonintransporter (SERT) or norepinephrine transporter (NET). In anotherexemplary embodiment, the compound of the invention inhibits theactivity of at least two different monoamine transporters Inhibition ofmonoamine transporter activity may be measured using assays known in theart. Exemplary assay formats include in vitro functional uptake assays.In an exemplary embodiment, the functional uptake assay utilizes anappropriate cell-line expressing a desired monoamine transporter. Inanother exemplary embodiment, the functional uptake assay utilizessynaptosomes isolated from brain tissue of an appropriate organism.Alternatively, inhibition of monoamine transporter activity may beassessed using receptor binding experiments known in the art, e.g.,utilizing appropriate membrane preparations. Another assay involvestreatment of a test subject (e.g., a rat) with a compound of theinvention as well as a reference compound, followed by isolation ofbrain tissue and ex vivo analysis of receptor occupancy, as describedherein.

D. Inhibition of Monoamine Uptake

In yet another aspect, the invention provides a method of inhibitinguptake of at least one monoamine (e.g., dopamine, serotonin,norepinephrine) by a cell. The method includes contacting the cell witha compound of the invention. In an exemplary embodiment, the cell is abrain cell, such as a neuron or a glial cell. In one example, inhibitionof monoamine uptake occurs in vivo. In an organism, neuronal uptake(also termed reuptake) of a monoamine such as dopamine or serotoninoccurs, for example, from the synaptic cleft. Thus, in one embodiment,the neuronal cell is in contact with a synaptic cleft of a mammal. Inanother exemplary embodiment, inhibition of monoamine uptake occurs invitro. In those methods the cell, may be a brain cell, such as aneuronal cell or a cell-type, which expresses a recombinant monoaminetransporter.

In one embodiment, the compound inhibits uptake of at least twodifferent monoamines. This can, for example, be shown by performingvarious in vitro functional uptake assays utilizing a cell-type, whichsimultaneously expresses multiple different monoamine transporters (suchas isolated synaptosomes), or may be shown by using two different celltypes, each expressing a different monoamine transporter, such as arecombinant dopamine transporter, together with an appropriate, labelledmonoamine. Inhibition of monoamine uptake is demonstrated when theinhibitor (e.g., a compound of the invention) has an IC₅₀ of betweenabout 0.1 nM and about 10 μM, preferably between about 1 nM and about 1μM, more preferably between about 1 nM and about 500 nM, and even morepreferably between about 1 nM and about 100 nM in a functional monoamineuptake assay, such as those described herein below.

E. Treatment of CNS Disorders

In another aspect, the invention provides a method of treatingdepression by inhibiting the activity at least one monoaminetransporter. The method includes administering to a mammalian subject acompound of the invention. In an exemplary embodiment, the mammaliansubject is a human. In another exemplary embodiment, the compound of theinvention inhibits the activity of at least two different monoaminetransporters. For example, the compound of the invention inhibits theactivity of at least two of serotonin transporter, dopamine transporterand norepinephrine transporter. Inhibition of monoamine transporteractivity may be shown by functional monoamine uptake assays as describedherein below. Demonstration of anti-depressant activity of a compound ofthe invention may be shown by utilizing an appropriate animal model ofdepression, such as the Rat Forced Swim Test, the Mouse Tail SuspensionTest and Rat Locomotor Activity Analyses. The Rat Forced Swim Test isalso suitable for the analysis of compounds having activities againstmore than one monoamine transporter (mixed monoamine transporteractivity). For example, an increase in swimming activity is indicativeof serotonin reuptake inhibition, while an increase in climbing activityis indicative of norepinephrine reuptake inhibition. In a preferredembodiment, the compounds of the invention are active in at least oneanimal model, which can be used to measure anti-depressant-likeactivities, for instance those assessing immobility. In an exemplaryembodiment, the compounds of the invention are active when they inhibitmean immobility by between about 5% and about 90%, preferably betweenabout 10% and about 70% and more preferably between about 10% and about50% in at least one animal model, when compared to vehicle.

In yet another aspect, the invention provides a method of effecting ananti-depressant-like effect. The method includes administering to amammalian subject in need thereof a therapeutically effective amount ofa compound or composition of the invention, e.g., a compound accordingto Formula (I), or a pharmaceutically acceptable salt or solvatethereof. Anti-depressant-like effectes may be measured using an animalmodel of disease, such as those described herein.

In a further aspect, the invention provides a method of treating acentral nervous system disorder. The method includes administering to asubject in need thereof a therapeutically effective amount of acomposition or compound of the invention, e.g., a compound according toFormula (I), or a pharmaceutically acceptable salt or solvate thereof.In a preferred embodiment, the subject is a human.

In another exemplary embodiment, the central nervous system disorder isa member selected from the group consisting of depression (e.g., majordepressive disorder, bipolar disorder, unipolar disorder, dysthymia andseasonal affective disorder), cognitive deficits, fibromyalgia, pain(e.g., neuropathic pain), sleep related disorders (e.g., sleep apnea,insomnia, narcolepsy, cataplexy) including those sleep disorders, whichare produced by psychiatric conditions, chronic fatigue syndrom,attention deficit disorder (ADD), attention deficit hyperactivitydisorder (ADHD), restless leg syndrome, schizophrenia, anxieties (e.g.general anxiety disorder, social anxiety discorder, panic disorder),obsessive compulsive disorder, posttraumatic stress disorder, seasonalaffective disorder (SAD), premenstrual dysphoria, post-menopausalvasomotor symptoms (e.g., hot flashes, night sweats), andneurodegenerative disease (e.g., Parkinson's disease, Alzheimer'sdisease and amyotrophic lateral sclerosis), manic conditions, dysthymicdisorder, and cyclothymic disorder. In a preferred embodiment, the CNSdisorder is depression, such as major depressive disorder. In anexemplary embodiment, the compounds of the invention are useful to treattwo conditions/disorders, which are comorbid, such as cognitive defictand depression.

Central nervous system disorder includes cerebral function disorders,including without limitation, senile dementia, Alzheimer's typedementia, cognition, memory loss, amnesia/amnestic syndrome, epilepsy,disturbances of consciousness, coma, lowering of attention, speechdisorders, Lennox syndrome, autism, and hyperkinetic syndrome.

Neuropathic pain includes without limitation post herpetic (orpost-shingles) neuralgia, reflex sympathetic dystrophy/causalgia ornerve trauma, phantom limb pain, carpal tunnel syndrome, and peripheralneuropathy (such as diabetic neuropathy or neuropathy arising fromchronic alcohol use).

Other exemplary diseases and conditions that may be treated using themethods of the invention include obesity; migraine or migraine headache;urinary incontinence, including without limitation involuntary voidingof urine, dribbling or leakage of urine, stress urinary incontinence(SUI), urge incontinence, urinary exertional incontinence, reflexincontinence, passive incontinence, and overflow incontinence; as wellas sexual dysfunction, in men or women, including without limitationsexual dysfunction caused by psychological and/or physiological factors,erectile dysfunction, premature ejaculation, vaginal dryness, lack ofsexual excitement, inability to obtain orgasm, and psycho-sexualdysfunction, including without limitation, inhibited sexual desire,inhibited sexual excitement, inhibited female orgasm, inhibited maleorgasm, functional dysparcunia, functional vaginismus, and atypicalpsychosexual dysfunction.

Selected compounds of the invention were evaluated in the mouse tailsuspension and locomotor activity test, which showed that the testedcompounds exhibited an antidepressant-like profile (i.e., significantlydecreased immobility time). At doses active in the tail suspension test,no change or a decrease in baseline motor activity was observedindicating that antidepressant-like activity was not due to a generalstimulant effect.

Selected compounds of the invention were also evaluated in the ratforced swim and locomotor activity tests. The decrease in immobilityproduced by these compounds appeared to be due to increases in swimmingand climbing behaviors indicative of mixed transporter activity (i.e.,SNRI profiles). In conclusion, the tested compounds of the inventionexibited an anti-depressant profile in at least three animal models, themouse tail suspension test and rat locomotor activity test as well asthe rat forced swim test.

The following examples are provided to illustrate selected embodimentsof the invention and are not to be construed as limiting its scope.

EXAMPLES 1. General Procedures

In the examples, below, the following general experimental procedureswere used unless otherwise noted: All commercial reagents were usedwithout further purification. Anhydrous reactions were performed inflame-dried glassware under N₂. NMR spectra were recorded on a Varian400 MHz spectrometer in deuterochloroform or methanol-d⁴ withtrimethylsilane (TMS) as an internal reference. Silica gel columnchromatography was performed using an ISCO Combiflash system withdetection at 254 nm or using ISCO normal phase silica gel cartridges.

Analytical HPLC

Analytical HPLC was performed on a Hewlett Packard Series 1100 pumpconnected to an Agilent Zorbax RX-C18 5 4.6×250 mm column, withdetection on a Hewlett Packard Series 1100 UV/Vis detector monitoring at214 and 254 nm. Typical flow rate=1 ml/min. Three different HPLC columnsand various elution protocols were used. For example, (1) Agilent ZorbaxRX-C18 5 μm, 4.6×250 mm column running a linear gradient. Solvent A=H₂Ow/0.05% TFA, Solvent B=MeCN w/0.05% TFA. Time 0 min=5% Solvent B, time 4min=40% Solvent B, time 8 min=100% Solvent B, 12 min=5% Solvent B, 20min=5% Solvent B; (2) Phenomenex 3μ C18 column running a 3 minutegradient of 5→100% B (acetonitrile/0.1% formic acid) and solvent A(water/0.1% formic acid); (3) Phenomenex 5μ C18 column running a 5minute gradient of 5→100% B where solvent B (acetonitrile/0.1% formicacid) and solvent A (water/0.1% formic acid).

Reverse Phase HPLC Purification

Reverse phase HPLC purification was performed on a Gilson system using aPhenomenex 5μ C18 (50×21.2 mm) column. The standard separation methodwas: 10 minute gradient of 10→100% B (acetonitrile/0.1% formic acid) insolvent A (water/0.1% formic acid). Crude samples were typicallydissolved in MeOH. Fractions were concentrated by Genovac(centrifugation at low pressure).

GC-MS

Gas chromatography was performed on a Hewlett Packard 6890 Series GCSystem with an HP1 column (30 meters, 0.15μ film thickness) coupled to aHewlett Packard 5973 Series Mass Selective Detector. The followinglinear temperature gradient was used: 100° C. for 5 minutes, then 20°C./min to 320° C. Hold @ 320° C. for 10 minutes.

LCMS

LCMS was performed on an Agilent 1100 Series system connected to aMicromass Platform LC. The following column and gradient was used:Column: Luna C18(2), 3 um particle size 30×2.0 mm column dimension. Flowrate=0.5 mL/min, Solvent A=0.1 M NH₄Ac in 95% H₂O, 5% MeOH, pH 6.0,Solvent B=Solvent B: 0.1 M NH₄Ac in MeOH. Linear gradient with 6entries: Time 0 min=100% Solvent A, time 10 min=100% Solvent B, time 12min=100% Solvent B, time 12 min 10 sec=100% Solvent A, time 14 min=100%Solvent A, time 14 min 20 sec=100% Solvent A.

Microwave (μW) Recrystallization

The crude salt (e.g., HCl salt) was loaded into a microwave vessel witha stir bar. The recrystallization solvent was added and the vessel washeated at the target temperature for a given time. The vessel was cooledto 50° C. in the reactor, was then removed and allowed to slowly cool toRT. N,N-dimethyl amines were typically recrystallized in EtOAc orEtOAc:CH₃CN (2:1). N-Me or primary amines were typically recrystallizedin CH₃CN. mixture was stirred at 25° C. for 18 h. The mixture was cooledto 15° C. and quenched with sat. aq. NH₄Cl (100 mL). The resultingmixture was partitioned between H₂O (1.2 L) and t-butyl methyl ether(MTBE) (300 mL). The aqueous layer was further extracted with MTBE (200mL). The combined organic layers were washed with brine (200 mL), driedover MgSO₄ (5 g) and spin-evaporated in vacuo to an oil. The oil waschromatographed on a silica gel column (1.0 kg) packed in, and elutedwith hexanes-EtOAc (4:1) (8.0 L). Appropriate fractions as determined byTLC were combined and spin-evaporated in vacuo to an oil, whichsolidified when pumped down, giving 27.4 g (97.0%) of purified product.A total of 240.2 g of product suitable for further transformation wasprepared in this fashion.

Example 1 Generic Procedure Synthesis of Cycloalkyl Pyrrolidine

A: Cyclization

To a solution of 1 (50 mmoL) in THF (200 mL)-NaOH (50%, 100 mL) at 0° C.was added TBAI (tetra-butylammonium iodide, 2.0 g) and dibromoalkane (60mmoL). The reaction mixture was stirred for 12 h before beingconcentrated. The product was extracted with diethyl ether (200 mL×3).The combined extracts were dried and concentrated. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate,gradient: 0/100 to 50/50) to give the desired product (˜85-95%).

B: Reduction and Wittig Reaction:

To a solution of 2 (40 mmoL) in CH₂Cl₂ (250 mL) at −78° C. was addedDibal-H (1.0 M in hexane, 48 mL, 48 mmoL). The reaction mixture wasstirred for 20 min before being quenched by MeOH (40 mL) and HCl (6 N,200 mL). The product was extracted with diethyl ether (200 mL×2). Thecombined extracts were dried and concentrated. The residue was used inthe next step without further purification.

To a solution of the residue from the above reaction in toluene (250 mL)was added the Wittig reagent (60 mmoL). The reaction mixture was stirredat 100° C. for 7 h before being concentrated. The resultant residue waspurified by silica gel column chromatography (hexane/ethyl acetate,gradient: 0/100 to 60/40) to give the desired product 4 (˜90% for twosteps).

C: Sodium Cyanide Addition:

To a solution of 4 (30 mmoL) in DMF (150 mL) and NaHCO₃ (saturated, 10mL) at room temperature was added NaCN (120 mmoL). The reaction mixturewas stirred for 16 h before being concentrated. The resultant residuewas acidified with HCl (4 N, 150 mL). The product was extracted withCH₂Cl₂ (200 mL×3). The combined extracts were dried and concentrated.The resultant residue was used in the next step without furtherpurification.

D: Borane Reduction

To a solution of the residue from the above reaction in THF (150 mL) wasadded BH₃.THF (1.0 M in THF, 200 mL, 200 mmoL) at room temperature. Thereaction mixture was stirred 14 h before being concentrated. Theresultant residue was quenched by MeOH (100 mL). The resultant mixturewas concentrated and purified by silica gel column chromatography (ethylacetate/MeOH/NH₃, gradient: 100/0/2 to 70/30/5) to give the desiredproduct 6 (˜79% for two steps).

F: Cyclization of Amino Alcohol:

To a solution of 6 (10 mmoL) in CH₂Cl₂ (100 mL) was slowly added SOCl₂(20 mmoL) at 0° C. The reaction mixture was stirred for 2 h before beingconcentrated. The residue was dissolved in CH₂Cl₂ (100 mL) and washedwith NaOH solution (6 N, 10 mL). The organic layer was separated. Theaqueous layer was extract with CH₂Cl₂ (100 mL×2). The combined extractswere dried and concentrated. The residue was used in the next stepwithout further purification.

Generic Method F for Chiral Separation:

F: Protection of Amine with Boc Group and Purification (for Ar=Naphthyl,n=1, 2, 3; Ar=3,4-Dichlorophenyl, n=2,3):

To a solution of 7 (8 mL) from the above reaction in CH₂Cl₂ (30 mL) wasadded Et₃N (12 mmoL) and (BOC)₂O (10 mmoL) The reaction mixture wasstirred for 2 h at room temperature before being quenched by NH₄Cl(saturated, 100 mL). The organic layer was separated. The aqueous layerwas extract with CH₂Cl₂ (50 mL×2). The combined extracts were dried andconcentrated. The residue was purified by silica gel columnchromatography (Hexane/ethyl acetate, gradient: 100/0 to 50/50) to givethe desired product 8 (˜86%).

The two enantiomers of 8 were separated by chiral column; the conditionsfor these and other compounds of the invention are summarized in thefollowing table. Scheme 2, shows a representative separation of twoenantiomers and the subsequent deprotection of the purified enantiomers.Compound numbers in this table and throughout the examples are withreference to Table 1, supra.

Separation Conditions

Chiral Compounds column Eluent Enantiomers Ar = 3,4 RO1iPrOH/Heptane/DEA =  1 (first peak) dichlorophenyl 10:90:0.1  2 (secondpeak) n = 3 Ar = 3,4 AD Hexane/iPrOH/DEA =  5 (first peak)dichlorophenyl 93/7/0.1  6 (second peak) n = 2 Ar = 2-naphthyl ADHexane/iPrOH/DEA =  9 (first peak) n = 3 95/5/0.1 10 (second peak) Ar =2-naphthyl AD Hexane/iPrOH/DEA = 11 (first peak) n = 2 90/10/0.1 12(second peak) Ar = 2-naphthyl RO1 Hexane/iPrOH/DEA = 13 (first peak) n =1 90/10/0.1 14 (second peak)

G: Deprotection of Boc Group:

To a solution of the N-Boc enantiomer (4 mmoL) in CH₂Cl₂ (10 mL) wasadded TFA (3 mL). The reaction mixture was stirred for 20 min beforebeing concentrated. The residue was purified by reverse phase columnchromatography to give the pure enantiomers.

H: Protection of Amine with Troc Group and Purification (forAr=3,4-Dichlorophenyl, n=1, R=Troc)

To a solution of 7 (8 mL) from the above reaction in CH₂Cl₂ (30 mL) wasadded Et₃N (12 mmoL) and TrocCl (10 mmoL). The reaction mixture wasstirred for 2 h at room temperature before being quenched by NH₄Cl(saturated, 100 mL). The organic layer was separated. The aqueous layerwas extract with CH₂Cl₂ (50 mL×2). The combined extracts were dried andconcentrated. The residue was purified by silica gel columnchromatography (Hexane/ethyl acetate, gradient: 100/0 to 50/50) to givethe desired product 8 (˜90%).

Crude 8 was separated by chiral column (eluent:Hexane/iPrOH/DEA=93/7/0.1 to give the two enantiomers (First peak isN-Troc protected 8, second peak is N-Troc protected 7).

I: Deprotection of N-Troc Group:

To a solution of the N-Troc enantiomer (4 mmoL) in THF (10 mL) was addedNH₄Cl (saturated, 2 mL) and Zn dust (12 mmol). The reaction mixture wasstirred for 2 h before the solid was filtered. The filtrate wasconcentrated. The residue was purified by reverse phase columnchromatography to give the pure enantiomers.

J: Reductive Amination:

To a solution of the amine 11 or 12 (3 mmol) in MeOH (6 mL) was addedHCHO (37% in water, 2 mL), HCO₂H (0.5 mL) and NaB(CN)H₃ (6 mmol). Thereaction was stirred for about 30 min before being concentrated. Theresulting residue was purified by reverse phase column chromatography(CH₃CN/H₂O, gradient, 10% to 100% CH₃CN in 10 min) to give pure 13 or 14((˜80%).

TABLE 2 Compounds Generic Cpd. No. Structure Methods Data 1

A B C D E F G ¹H NMR (400 MHz, CD₃OD) δ 7.53 (m, 2 H), 7.33 (d, J = 8.4Hz, 1 H), 3.24 (m, 1 H), 3.16 (m, 2 H), 2.73 (t, J = 11.6 Hz, 1 H),2.42-2.28 (m, 3 H), 1.93- 1.88 (m, 1 H), 1.62-1.59 (m, 6 H), 1.32- 1.21(m, 3 H); ¹³C NMR (100 MHz, CD₃OD) δ 143.19, 132.45, 130.46, 130.33,130.11, 128.25, 50.28, 45.46, 44.86, 44.58, 33.80, 33.64, 26.21, 24.96,21.92; ESI MS + 1 m/z 299. 2

A B C D E F G ¹H NMR (400 MHz, CD₃OD) δ 7.53 (m, 2 H), 7.33 (d, J = 8.4Hz, 1 H), 3.24 (m, 1 H), 3.16 (m, 2 H), 2.73 (t, J = 11.6 Hz, 1 H),2.42-2.28 (m, 3 H), 1.93- 1.88 (m, 1 H), 1.62-1.59 (m, 6 H), 1.32- 1.21(m, 3 H); ¹³C NMR (100 MHz, CD₃OD) δ 143.19, 132.45, 130.46, 130.33,130.11, 128.25, 50.28, 45.46, 44.86, 44.58, 33.80, 33.64, 26.21, 24.96,21.92; ESI MS + 1 m/z 299. 3

A B C D E F G J ¹H NMR (400 MHz, CD₃OD) δ 7.48 (d, J = 2.0 Hz, 1 H),7.47 (d, J = 8.8 Hz, 1 H), 7.30 (dd, J = 2.0, 8.8 Hz, 1 H), 2.7- 2.64(m, 1 H), 2.56 (t, J = 8.4 Hz, 1 H), 2.34-2.27 (m, 1 H), 2.24 (s, 3 H),2.24- 2.18 (m, 2 H), 2.18-2.13 (m, 1 H), 1.70- 1.50 (m, 1 H), 1.38-1.10(m, 4 H); ¹³C NMR (100 MHz, CD₃OD) δ 144.97, 138.85, 132.04, 130.23,130.08, 128.16, 56.55, 55.61, 50.82, 43.34, 41.33, 33.44, 32.95, 26.45,25.45, 22.03; ESI MS + 1 m/z 312. 4

A B C D E F G J ¹H NMR (400 MHz, CD₃OD) δ 7.48 (d, J = 2.0 Hz, 1 H),7.47 (d, J = 8.8 Hz, 1 H), 7.30 (dd, J = 2.0, 8.8 Hz, 1 H), 2.7- 2.64(m, 1 H), 2.56 (t, J = 8.4 Hz, 1 H), 2.34-2.27 (m, 1 H), 2.24 (s, 3 H),2.24- 2.18 (m, 2 H), 2.18-2.13 (m, 1 H), 1.70- 1.50 (m, 1 H), 1.38-1.10(m, 4 H); ¹³C NMR (100 MHz, CD₃OD) δ 144.97, 138.85, 132.04, 130.23,130.08, 128.16, 56.55, 55.61, 50.82, 43.34, 41.33, 33.44, 32.95, 26.45,25.45, 22.03; ESI MS + 1 m/z 312. 5

A B C D E F G ¹H NMR (400 MHz, CD₃OD) δ 7.52 (d, J = 2.0 Hz, 1 H), 7.48(d, J = 8.4 Hz, 1 H), 7.32 (dd, J = 2.0 Hz, 1H), 3.232- 3.28 (m, 2 H),3.22-3.15 (m, 2 H), 2.75- 2.60 (m, 2 H), 2.12-2.05 (m, 2 H), 2.05-1.90(m, 2 H), 1.85-1.70 (m, 2 H), 1.64-1.50 (m, 2 H); ¹³C NMR (100 MHz,CD₃OD) δ 145.82, 132.07, 130.19, 129.82, 130.11, 127.77, 51.39, 47.22,46.63, 45.09, 35.58, 26.40, 22.70, 22.64; ESI MS + 1 m/z 284. 6

A B C D E F G ¹H NMR (400 MHz, CD₃OD) δ 7.52 (d, J = 2.0 Hz, 1 H), 7.48(d, J = 8.4 Hz, 1 H), 7.32 (dd, J = 2.0 Hz, 1H), 3.232- 3.28 (m, 2 H),3.22-3.15 (m, 2 H), 2.75- 2.60 (m, 2 H), 2.12-2.05 (m, 2 H), 2.05-1.90(m, 2 H), 1.85-1.70 (m, 2 H), 1.64-1.50 (m, 2 H); ¹³C NMR (100 MHz,CD₃OD) δ 145.82, 132.07, 130.19, 129.82, 130.11, 127.77, 51.39, 47.22,46.63, 45.09, 35.58, 26.40, 22.70, 22.64; ESI MS + 1 m/z 284. 7

A B C D E H I ¹H NMR (400 MHz, CD₃OD) δ 7.47 (d, J = 8.8 Hz, 1 H), 7.34(s, 1 H), 7.12 (d, J = 8.8 Hz, 1H), 3.30-3.19 (m, 3 H), 2.85-2.71 (m, 2H), 2.39 (m, 4 H), 2.08-1.89 (m, 2 H), 1.87 (m, 1 H), 1.70 (m, 1 H); ¹³CNMR (100 MHz, CD₃OD) δ 148.94, 132.00, 130.25, 129.80, 128.59, 126.48,47.63, 46.18, 46.13, 45.16, 31.09, 30.74, 26.01, 15.38; ESI MS + 1 m/z270. 8

A B C D E H I ¹H NMR (400 MHz, CD₃OD) δ 7.47 (d, J = 8.8 Hz, 1 H), 7.34(s, 1 H), 7.12 (d, J = 8.8 Hz, 1H), 3.30-3.19 (m, 3 H), 2.85-2.71 (m, 2H), 2.39 (m, 4 H), 2.08-1.89 (m, 2 H), 1.87 (m, 1 H), 1.70 (m, 1 H); ¹³CNMR (100 MHz, CD₃OD) δ 148.94, 132.00, 130.25, 129.80, 128.59, 126.48,47.63, 46.18, 46.13, 45.16, 31.09, 30.74, 26.01, 15.38; ESI MS + 1 m/z272. 9

A B C D E F G ¹H NMR (400 MHz, CD₃OD) δ 7.92- 7.81 (m, 4 H), 7.58-7.52(m, 1 H), 7.50- 7.40 (m, 2 H), 3.28-3.20 (m, 1 H), 3.18-3.02 (m, 2 H),2.86-2.78 (m, 1 H), 2.60-2.40 (m, 3 H), 2.04-1.94 (m, 1 H), 1.72-1.50(m, 5 H), 1.40-1.28 (m, 2 H); ¹³C NMR (100 MHz, CD₃OD) δ 138.81, 133.79,132.24, 127.97, 127.88, 127.41, 127.14, 125.96, 125.84, 125.83, 50.69,45.73, 44.98, 42.72, 34.55, 34.03, 26.38, 23.11, 22.11; ESI MS + 1 m/z279. 10

A B C D E F G ¹H NMR (400 MHz, CD₃OD) δ 7.92- 7.81 (m, 4 H), 7.58-7.52(m, 1 H), 7.50- 7.40 (m, 2 H), 3.28-3.20 (m, 1 H), 3.18-3.02 (m, 2 H),2.86-2.78 (m, 1 H), 2.60-2.40 (m, 3 H), 2.04-1.94 (m, 1 H), 1.72-1.50(m, 5 H), 1.40-1.28 (m, 2 H); ¹³C NMR (100 MHz, CD₃OD) δ 138.81, 133.79,132.24, 127.97, 127.88, 127.41, 127.14, 125.96, 125.84, 125.83, 50.69,45.73, 44.98, 42.72, 34.55, 34.03, 26.38, 23.11, 22.11; ESI MS + 1 m/z279. 11

A B C D E F G ¹H NMR (400 MHz, CD₃OD) δ 7.91- 7.70 (m, 4 H), 7.51-7.41(m, 3 H), 7.50- 7.40 (m, 2 H), 5.0 (broad, 1 H), 3.32- 3.24 (m, 1 H),3.14-3.02 (m, 2 H), 2.82- 2.64 (m, 2 H), 2.24-2.14 (m, 2 H), 2.00-1.88(m, 3 H), 1.80-1.70 (m, 2 H), 1.70-1.50 (m, 3 H); ¹³C NMR (100 MHz,CD₃OD) δ 141.82, 133.50, 132.39, 127.92, 127.81, 127.23, 126.21, 126.05,125.78, 51.58, 46.89, 46.77, 36.17, 35.59, 22.87, 22.82; ESI MS + 1 m/z265. 12

A B C D E F G ¹H NMR (400 MHz, CD₃OD) δ 7.91- 7.70 (m, 4 H), 7.51-7.41(m, 3 H), 7.50- 7.40 (m, 2 H), 5.0 (broad, 1 H), 3.32- 3.24 (m, 1 H),3.14-3.02 (m, 2 H), 2.82- 2.64 (m, 2 H), 2.24-2.14 (m, 2 H), 2.00-1.88(m, 3 H), 1.80-1.70 (m, 2 H), 1.70-1.50 (m, 3 H); ¹³C NMR (100 MHz,CD₃OD) δ 141.82, 133.50, 132.39, 127.92, 127.81, 127.23, 126.21, 126.05,125.78, 51.58, 46.89, 46.77, 36.17, 35.59, 22.87, 22.82; ESI MS + 1 m/z265. 13

A B C D E F G ¹H NMR (400 MHz, CD₃OD) δ 7.84- 7.80 (m, 3 H), 7.62 (s, 1H), 7.48-7.42 (m, 2 H), 7.32-7.29 (m, 1 H), 4.90 (broad, 1 H), 3.30-3.28(m, 1 H), 3.16- 3.13 (m, 2 H), 2.87-2.86 (m, 2 H), 2.60-2.52 (m, 2 H),2.46-2.41 (m, 2 H), 2.15-2.06 (m, 2 H), 1.96-1.90 (m, 1 H), 1.90-1.71(m, 1 H); ¹³C NMR (100 MHz, CD₃OD) δ 144.69, 133.44, 132.27, 127.90,127.63, 127.39, 126.12, 125.62, 124.80, 124.77, 47.80, 46.60; ESI MS + 1m/z 252. 14

A B C D E F G ¹H NMR (400 MHz, CD₃OD) δ 7.84- 7.80 (m, 3 H), 7.62 (s, 1H), 7.48-7.42 (m, 2 H), 7.32-7.29 (m, 1 H), 4.90 (broad, 1 H), 3.30-3.28(m, 1 H), 3.16- 3.13 (m, 2 H), 2.87-2.86 (m, 2 H), 2.60-2.52 (m, 2 H),2.46-2.41 (m, 2 H), 2.15-2.06 (m, 2 H), 1.96-1.90 (m, 1 H), 1.90-1.71(m, 1 H); ¹³C NMR (100 MHz, CD₃OD) δ 144.69, 133.44, 132.27, 127.90,127.63, 127.39, 126.12, 125.62, 124.80, 124.77, 47.80, 46.60; ESI MS + 1m/z 252.

Scheme 2 sets forth an exemplary route to synthesis of cylic etherpyrrolidines of the invention, e.g., 15 and 16.

Table 3 provides exemplary structures and analytical characteristics ofrepresentative cyclic ether pyrrolidines of the invention.

TABLE 3

Cpd. Generic No. Ar X R Methods Data 15

O H A B C D E F G ¹H NMR (400 MHz, CD₃OD) δ 7.59-7.56 (m, 2 H), 7.36 (d,J = 16.8 Hz, 1 H), 3.79 (d, J = 11.2 Hz, 2 H), 3.39-3.26 (m, 5 H). 2.76(t, J = 11.6 Hz, 1 H), 2.76 (t, J = 11.6 Hz, 1 H), 2.57 (m, 1 H), 2.32-2.25 (m, 2 H), 1.99-1.89 (m, 3 H), 1.60-1.55 (m, 1 H); ¹³C NMR (100 MHz,CD₃OD) δ 141.83, 132.82, 130.79,130.39, 128.30, 63.83, 63.76, 49.31,45.33, 45.09, 40.77, 34.02, 33.75, 24.85; ESI MS + 1 m/z 300. 16

O H A B C D E F G 1H NMR (400 MHz, CD₃OD) δ 7.59-7.56 (m, 2 H), 7.36 (d,J = 6.8 Hz, 1 H), 3.79 (d, J = 11.2 Hz, 2 H), 3.39-3.26 (m, 5 H). 2.76(t, J = 11.6 Hz, 1 H), 2.76 (t, J = 11.6 Hz, 1 H), 2.57 (m, 1 H), 2.32-2.25 (m, 2 H), 1.99-1.89 (m, 3 H), 1.60-1.55 (m, 1 H); ¹³C NMR (100 MHz,CD₃OD) δ 141.83, 132.82, 130.79, 130.39, 128.30, 63.83, 63.76, 49.31,45.33, 45.09, 40.77, 34.02, 33.75, 24.85; ESI MS + 1 m/z 300.

Scheme 3 provides an exemplary route to substituted cycloalkylderivatives of the invention through a ketone precursor. Generalprocedures B, C, F, E were used to prepare compound 21.

K: Selective Deprotection of the Ketone.

To a solution of 21 (7 g, 15.4 mmol) in a mixture of THF (20 mL) and H₂O(50 mL) was added AcOH (150 mL). The reaction mixture was stirred at 80°C. for 1.5 h before being concentrated at reduced pressure. The residuewas purified by silica gel column chromatography (gradient, Hexane/ethylacetate from 100:0 to 0:100) to give 22 (4.69 g, 74%) and recoveredstarting material (1.3 g).

L: 1,2 Addition of MeMgBr to Ketone and Deprotection:

The following steps are illustrated in Scheme 4. To a solution of 22(4.0 g, 9.7 mmoL) in THF (40 mL) at −78° C. was added MeMgBr (3 M indiethyl ether, 19.4 mmoL, 6.4 mL). The reaction mixture was stirred for10 min before being quenched by saturated NH₄Cl (20 mL). The product wasextracted with CH₂Cl₂ (100 mL×3), dried and concentrated. The residuewas then purified by silica gel column chromatography (gradient,Hexane/ethyl acetate from 100:0 to 0:100) to give a mixture of 23, 24,25, 26 (3.6 g,). The mixture was separated by chiral column (RO1, 7.5%IHD). The enantiomer 23 (first peak) and 26 (last peak) were obtained.The mixture of 24 and 25 (the second peak) was further separated bychiral RO1 column (5% EHD as eluent) to give 24 (the first peak) and 25(the second peak). Deprotection of N-Boc groups in 23, 24, 25, 26 withTFA afforded 20, 19, 18 and 17.

M: Reduction of Ketone and Deprotection:

Treatment of compound 22 with N-Selectride in CH₂Cl₂ at −78° C. gave thetwo pairs of racemic compounds Rac1 and Rac2 (ratio of Rac1:Rac2=1:1.5).Separation of the four compounds with RO1 (5% EHD as eleut) provided 27(the first peak), a mixture of 28 and 29 (the second peak), and 30 (thethird peak). 28 and 29 were then separated by reverse phase (MeCN/H₂O,gradient, from 5% MeCN to 100% MeCN). Deprotection of the N-Boc group in27, 28, 29 and 30 afforded the compounds 21, 22, 23 and 24.

Scheme 4 provides an exemplary route to the reduction of the cycloalkylketone and the resolution of the resulting mixture of stereoisomers.

N: Methylation and Deprotection:

Scheme 5 sets forth an exemplary route to methylation and deprotectionof various substrates to form compounds of the invention. Treatment ofcompounds 23, 24, 25, 26 with NaH and iodomethane provided methylatedcompounds 31, 32, 33, 34 respectively. Removal of the N-Boc protectinggroups afforded 25, 26, 27 and 28.

Table 4 sets forth structures of exemplary compounds of the invention,the generic procedures used to synthesize them, and analytical dataacquired from these compounds.

TABLE 4

Cpd. Generic No. R₁ R₂ R₃ Methods Data 17 Me OH H B ¹H NMR (400 MHz,CD₃OD) δ C 7.58-7.54 (m, 2 H), 7.39-7.37 (m, 1 F H), 3.21-3.08 (m, 2 H),2.80-2.70 E (m, 1 H), 2.70-2.55 (m, 1 H), 2.40- K 2.20 (m, 2 H),2.05-1.85 (m, 2 H), L 1.80-1.62 (m, 2 H), 1.62-1.40 (m, 5 H), 1.27 (m, 3H); ¹³C NMR (100 MHz, DMSO) δ 154.08, 131.59, 130.69, 130.65, 129.27,129.17, 46.74, 45.99, 45.74, 40.85, 40.62, 39.58, 36.38, 31.99, 31.20,27.56, 26.69; ESI MS + 1 m/z 328. 18 Me OH H B 1H NMR (400 MHz, CD₃C1₃)δ C 7.58-7.54 (m, 2 H), 7.39-7.37 (m, 1 F H), 3.21-3.08 (m, 2 H),2.80-2.70 E (m, 1 H), 2.70-2.55 (m, 1 H), 2.40- K 2.20 (m, 2 H),2.05-1.85 (m, 2 H), L 1.80-1.62 (m, 2 H), 1.62-1.40 (m, 5 H), 1.27 (m, 3H); ¹³C NMR (100 MHz, DMSO) δ 154.08, 131.59, 130.69, 130.65, 129.27,129.17, 46.74, 45.99, 45.74, 40.85, 40.62, 39.58, 36.38, 31.99, 31.20,27.56, 26.69; ESI MS + 1 m/z 328. 19 Me OH H B ¹H NMR (400 MHz, DMSO) δ7.55 C (m, 2 H), 7.46 (m, 1 H), 3.30-3.00 F (m, 3 H), 2.90-2.70 (m, 1H), 2.45- E 2.25 (m, 1 H), 2.20-2.00 (m, 2 H), K 2.00-1.80 (m, 3 H),1.70-1.40 (m, 3 L H), 1.16-1.05 (m, 3 H), 1.01 (s, 3 H); ¹³C NMR (100MHz, DMSO) δ 143.46, 131.91, 131.02, 130.74, 129.55, 129.26, 67.42,50.53, 45.43, 44.69, 42.52, 40.86, 40.61, 35.24, 31.74, 26.82, 23.56;ESI MS + 1 m/z 328. 20 Me OH H B ¹H NMR (400 MHz, CD₃OD) δ 7.55 C (m, 2H), 7.46 (m, 1 H), 3.30-3.00 F (m, 3 H), 2.90-2.70 (m, 1 H), 2.45- E2.25 (m, 1 H), 2.20-2.00 (m, 2 H), K 2.00-1.80 (m, 3 H), 1.70-1.40 (m, 3L H), 1.16-1.05 (m, 3 H), 1.01 (s, 3 H); ¹³C NMR (100 MHz, CD₃OD) δ143.46, 131.91, 131.02, 130.74, 129.55, 129.26, 67.42, 50.53, 45.43,44.69, 42.52, 40.86, 40.61, 35.24, 31.74, 26.82, 23.56; ESI MS + 1 m/z328. 21 H OH H B ¹H NMR (400 MHz, CD3OD) δ 7.54 C (d, J = 2.0 Hz, 1 H),7.52 (d, J = 8.8 F Hz, 1 H), 7.33 (dd, J = 8.8, 2.0 Hz, 1 E H), 5.0(broad, 2 H), 3.70-3.61 (m, 1 K H), 3.61-3.54 (m, 1 H), 3.36-3.35 M (m,1 H), 3.13 (d, J = 12.8 Hz, 1 H), 2.43-2.34 (m, 3 H), 2.00-1.96 (m, 1H), 1.84-1.74 (m, 2 H), 1.74-1.64 (m, 1 H), 1.64-1.55 (m, 3 H), 1.22-1.16 (m, 3 H); ¹³C NMR (100 MHz, CD₃OD) δ 143.10, 132.57, 130.51,130.30, 128.16, 69.97, 60.88, 47.47, 44.46, 41.56, 32.13, 31.06, 30.93,30.89, 30.56; ESI MS + 1 m/z 314. 22 H OH H B ¹H NMR (400 MHz, CD₃OD) δ7.54 C (d, J = 2.0 Hz, 1 H), 7.52 (d, J = 8.8 F Hz, 1 H), 7.33 (dd, J =8.8, 2.0 Hz, 1 E H), 5.0 (broad, 2 H), 3.70-3.61 (m, 1 K H), 3.61-3.54(m, 1 H), 3.36-3.35 M (m, 1 H), 3.13 (d, J = 12.8 Hz, 1 H), 2.43-2.34(m, 3 H), 2.00-1.96 (m, 1 H), 1.84-1.74 (m, 2 H), 1.74-1.64 (m, 1 H),1.64-1.55 (m, 3 H), 1.22- 1.16 (m, 3 H); ¹³C NMR (100 MHz, CD₃OD) δ143.10, 132.57, 130.51, 130.30, 128.16, 69.97, 60.88, 47.47, 44.46,41.56, 32.13, 31.06, 30.93, 30.89, 30.56; ESI MS + 1 m/z 314. 23 H OH HB ¹H NMR (400 MHz, CD₃Cl) δ 7.45 C (d, J = 8.0 Hz, 1 H), 7.34 (s, 1 H),F 7.11 (d, J = 8.0 Hz, 1 H), 3.65 (m, 1 E H), 3.35-3.05 (m, 2 H), 2.7(m, 1 H), K 2.40-2.20 (m, 2 H), 1.95-1.80 (m, 2 M H), 1.80-1.40 (m, 6H), 1.25-1.18 (m, 1 H); ¹³C NMR (100 MHz, DMSO) δ 143.67, 132.03,131.14, 130.85, 129.58, 129.36, 69.56, 50.08, 45.47, 44.65, 42.54,40.90, 39.65, 31.97, 31.88, 25.76; ESI MS + 1 m/z 314. 24 H OH H B ¹HNMR (400 MHz, CD₃Cl) δ 7.45 C (d, J = 8.0 Hz, 1 H), 7.34 (s, 1 H), F7.11 (d, J = 8.0 Hz, 1 H), 3.65 (m, 1 E H), 3.35-3.05 (m, 2 H), 2.7 (m,1 H), K 2.40-2.20 (m, 2 H), 1.95-1.80 (m, 2 M H), 1.80-1.40 (m, 6 H),1.25-1.18 (m, 1 H); ¹³C NMR (100 MHz, DMSO) δ 143.67, 132.03, 131.14,130.85, 129.58, 129.36, 69.56, 50.08, 45.47, 44.65, 42.54, 40.90, 39.65,31.97, 31.88, 25.76; ESI MS + 1 m/z 314. 25 Me OMe H B ¹H NMR (400 MHz,CD₃Cl) δ 7.43 C (d, J = 8.0 Hz, 1 H), 7.36 (d, J = 2.4 F Hz, 1 H), 7.13(dd, J = 8.4, 2.4 Hz, 1 E H), 3.15 (s, 3 H), 3.14-3.00 (m, 2 K H), 2.7(t, J = 11.2 Hz, 1 H), 2.33 (m, N 1 H), 2.0-1.90 (m, 3 H), 1.90-1.75 (m,3 H), 1.75-1.62 (m, 3 H), 1.62- 1.50 (m, 1H), 1.10-1.03 (m, 2 H), 0.95(s, 3 H); ¹³C NMR (100 MHz, CD₃Cl₃) δ 142.02, 133.23, 131.04, 130.90,129.81, 127.18, 72.44, 50.97, 48.77, 45.46, 44.60, 42.07, 31.68, 31.54,28.28, 25.49, 24.64; ESI MS + 1 m/z 342. 26 Me OMe H B ¹H NMR (400 MHz,CD₃Cl) δ 7.43 C (d, J = 8.0 Hz, 1 H), 7.36 (d, J = 2.4 F Hz, 1 H), 7.13(dd, J = 8.4, 2.4 Hz, 1 E H), 3.15 (s, 3 H), 3.14-3.00 (m, 2 K H), 2.7(t, J = 11.2 Hz, 1 H), 2.33 (m, N 1 H), 2.0-1.90 (m, 3 H), 1.90-1.75 (m,3 H), 1.75-1.62 (m, 3 H), 1.62- 1.50 (m, 1H), 1.10-1.03 (m, 2 H), 0.95(s, 3 H); ¹³C NMR (100 MHz, CD₃Cl₃) δ 142.02, 133.23, 131.04, 130.90,129.81, 127.18, 72.44, 50.97, 48.77, 45.46, 44.60, 42.07, 31.68, 31.54,28.28, 25.49, 24.64; ESI MS + 1 m/z 342 27 Me OMe H B ¹H NMR (400 MHz,CD₃OD) δ C 7.84-7.80 (m, 3 H), 7.62 (s, 1 H), F 7.48-7.42 (m, 2 H),7.32-7.29 (m, 1 E H), 4.90 (broad, 1 H), 3.30-3.28 (m, K 1 H), 3.16-3.13(m, 2 H), 2.87-2.86 N (m, 2 H), 2.60-2.52 (m, 2 H), 2.46- 2.41 (m, 2 H),2.15-2.06 (m, 2 H), 1.96-1.90 (m, 1 H), 1.90-1.71 (m, 1 H); ¹³C NMR (100MHz, CD₃OD) δ 144.69, 133.44, 132.27, 127.90, 127.63, 127.39, 126.12,125.62, 124.80, 124.77, 47.80, 46.60; ESI MS + 1 m/z 252. 28 Me OMe H B¹H NMR (400 MHz, CD₃OD) δ C 7.84-7.80 (m, 3 H), 7.62 (s, 1 H), F7.48-7.42 (m, 2 H), 7.32-7.29 (m, 1 E H), 4.90 (broad, 1 H), 3.30-3.28(m, K 1 H), 3.16-3.13 (m, 2 H), 2.87-2.86 N (m, 2 H), 2.60-2.52 (m, 2H), 2.46- 2.41 (m, 2 H), 2.15-2.06 (m, 2 H), 1.96-1.90 (m, 1 H),1.90-1.71 (m, 1 H); ¹³C NMR (100 MHz, CD₃OD) δ 144.69, 133.44, 132.27,127.90, 127.63, 127.39, 126.12, 125.62, 124.80, 124.77, 47.80, 46.60;ESI MS + 1 m/z 252.

O: RuCl₃—NaIO₄ Oxidation:

Scheme 6 sets forth an exemplary oxidateive route to compounds of theinvention utilizing ruthenium as the oxidant. To the compound 34 (3 g,7.8 mmol) in CH₃CN (100 mL) and H₂O (5 mL) was added RuCl₃.6H₂O (0.5 g)and NaI₄ (3.3 g, 15.7 mmol). The reaction mixture was stirred for 8 hbefore being concentrated. The residue was extracted with CH₂Cl₂ (3×50mL). The combined CH₂Cl₂ solution was dried and concentrated. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane, gradient, 0% to 100% ethyl acetate) to give the desiredproduct 36 (2.2 g, 72%).

P: Alpha-Hydroxylation:

To a solution of 36 (1.5 g, 3.8 mmol) in THF (30 mL) at −78° C. wasadded LiHMDS (1.0 M in THF, 5 mL, 5.00 mmol). The reaction mixture wasstirred for 1 h before a solution of(1S)-(+)-(10-Camphorsulfonyl)oxaziridine (5.0 mmol) in THF (15 mL) wasadded, followed by HMPA (1 mL). The reaction mixture was stirred for 2 hat −78° C. and then was warmed to −20° C. before being quenched bysaturated NH₄Cl solution (10 mL). The reaction mixture was thenconcentrated to remove most of THF. The product was extracted withCH₂Cl₂ (3×50 mL) and the combined CH₂Cl₂ extracts were dried andconcentrated. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane, gradient, 0% to 100% for ethylacetate) to give the desired product 37 (1.3 g, 85%).

Q: Removal of Boc Group

To a solution of 37 (1.0 g, 2.4 mmol), in CH₂Cl₂ (15 mL) was added TFA(5 mL). The reaction mixture was stirred for 30 min before beingconcentrated. The residue was dissolved in CH₂Cl₂ (30 mL), washed withNaOH (3 N, 3 mL), dried and concentrated to give 38 (0.69 g, 92%).

R: Borane Reduction of Lactam:

Scheme 7 provides an exemplary route to synthesis of a lactam and thereduction of that lactam with borane. To a solution of 38 (0.5 g, 1.6mmol) in THF was added BH₃.THF (1.0 M in THF, 6 mL, 6 mmol). Thereaction mixture was stirred at reflux for 8 h before beingconcentrated. The residue was dissolved in MeOH and purified by reversedphase HPLC to give 31 (0.4 g, 84%).

S: Methyl Addition to Cyano Group:

To a solution of 39 (9 g, 37.8 mmol) in THF (150 mL) at −10° C. wasadded MeMgCl (3 M in THF, 20 mL, 60 mmol). The reaction mixture wasstirred for 5 h at reflux before being quenched by NH₄Cl (20 mL). Theresulting mixture was concentrated to remove most of THF. The productwas then extracted with CH₂Cl₂ (2×100 mL). The combined extracts weredried and concentrated to give 40 (9 g, 95%).

T: Alpha Carboxylation:

To a solution of 40 (9.0 g, 35.2 mmol) in THF at −78° C. was addedLiHMDS (1.0 M in THF, 45 mL, 45 mmol) and HMPA (6 mL). The reactionmixture was stirred for 30 min before methyl cyanoformate (3.0 g, 35.2mmol) was added. The reaction mixture was stirred for 2 h at −78° C. andthen warmed to −10° C. over 30 min before being quenched by NH₄Cl (20mL). The resulting mixture was concentrated to remove most of THF. Theproduct was then extracted with CH₂Cl₂ (2×100 mL). The combined extractswere dried and concentrated. The resulting residue was purified bysilica gel column chromatography (ethyl acetate/hexane, gradient, 0% to100% for ethyl acetate) to give the desired product 41 (9.4 g, 85%).

U: Cyano Group Addition to Ketone and Chiral Separation:

To a solution of 41 (2.11 g, 6.7 mmol) in CH₂Cl₂ (30 mL) was added ZnI₂(12.8 g, 40.2 mmol) and Me₃SiCN (5.4 mL, 3.99 g, 40.2 mmol). Thereaction mixture was stirred overnight. The inorganic solid wasfiltered. The filtrate was washed with saturated NaHCO₃, dried andconcentrated. The resulting residue was purified by silica gel columnchromatography (ethyl acetate/hexane, gradient, 0% to 100% ethylacetate) to give the desired product 42 (2.3 g, 83%).

The racemic mixture of 42 (800 mg) was separated by chiral column RO1column with 5% MEHD as eluent to give 43 (the first peak, 300 mg) and 44(the second peak, 280 mg).

V: Reduction of Cyano Group and Cyclization:

To a solution of 43 (300 mg, 0.73 mmol) in MeOH (6 mL) was added CoCl₂.6H₂O (0.52 g, 2.19 mmoL) and NaBH₄ (220 mg, 5.84 mmol). The reactionmixture was stirred for 1 h before being concentrated. The residue waswashed with CH₂Cl₂ (3×30 mL). The combined CH₂Cl₂ solution was dried andconcentrated. Purification of the residue by reverse phase HPLC gave the45 (192 mg, 85%).

W: Borane Reduction and TMS Depreotection:

To a solution of 45 (150 mg, 0.47 mmol) in THF (5 mL) was added BH₃.THF(1.0 M in THF, 4 mL, 4.0 mmol). The reaction mixture was heated atreflux for 8 h before being concentrated. The residue was quenched byMeOH (2 mL). MeOH was removed and CH₂Cl₂ (5 mL) and TFA (3 mL) wereadded. The reaction mixture was stirred for 30 min before beingconcentrated. The residue was purified by reverse phase HPLC (CH₃CN/H₂O,gradient, 10% to 100% in 10 min for MeCN) to give 30 (112 mg, 85%).

Following steps V and W, 29 was obtained from 43. Table 5 sets forthstructures of representative compounds of the invention in which thepyrrolidne ring system is substituted.

TABLE 5

Cpd. Generic No. R₁ R₂ Methods Data 29 OH H S ¹H NMR (400 MHz, CDCl₃) δ7.49 T (d, J = 2.0 Hz, 1 H), 7.35 (d, J = 8.4 U Hz, 1 H), 7.27 (dd, J =2.0, 8.4 Hz, 1 V H), 3.36 (m, 3 H), 3.20 (m, 1 H), 3.00 W (s, 2H), 2.18(m, 2 H), 1.98 (m, 3 H), 1.78 (m, 3 H), 1.48 (m, 2 H); ¹³C NMR (100 MHz,CDCl₃) 144.50, 133.31, 132.21, 130.91, 129.97, 128.32, 83.66, 56.43,53.07, 43.57, 34.50, 34.56, 23.99, 23.96; ESI MS + 1 m/z 300. 30 OH H S¹H NMR (400 MHz, CDCl₃) δ 7.49 T (d, J = 2.0 Hz, 1 H), 7.35 (d, J = 8.4U Hz, 1 H), 7.27 (dd, J = 2.0, 8.4 Hz, 1 V H), 3.36 (m, 3 H), 3.20 (m, 1H), 3.00 W (s, 2H), 2.18 (m, 2 H), 1.98 (m, 3 H), 1.78 (m, 3 H), 1.48(m, 2 H); ¹³C NMR (100 MHz, CDCl₃) 144.50, 133.31, 132.21, 130.91,129.97, 128.32, 83.66, 56.43, 53.07, 43.57, 34.50, 34.56, 23.99, 23.96;ESI MS + 1 m/z 300. 31 H OH O ¹H NMR (400 MHz, CDCl₃) δ 7.40 P (d, J =8.4 Hz, 1 H), 7.37 (d, 7 = 2.0 Q Hz, 1 H), 7.14 (dd, J = 2.0, 8.4 Hz, 1R H), 4.16 (m, 1 H), 3.29 (m, 1 H), 3.09 (d, J = 11.6 Hz, 1H), 2.67-2.52(m, 3 H), 2.06-2.02 (m, 1 H), 2.02-1.84 (m, 5 H), 1.87-1.62 (m, 2 H);¹³C NMR (100 MHz, CDCl₃) 143.50, 133.10, 132.41, 130.63, 129.73, 127,72.21, 55.52, 54.10, 51.75, 47.13, 38.78, 37.09, 35.45, 23.05, 22.97;ESI MS + 1 m/z 300.

Example 2 In Vitro Analyses (Monoamine Uptake Assays)

The compounds of the invention were tested for their inhibition offunctional uptake of serotonin (5-HT), norepinephrine (NE), and dopamine(DA), in synaptosomes prepared from rat whole brain, hypothalamus, orcorpus striatum, respectively, and/or using recombinant humantransporters, as described herein, below. Compounds were initiallytested at 10 μM in duplicate. Compounds showing ≧50% inhibition ofuptake were further tested at 10 different concentrations in duplicatein order to obtain full inhibition curves. IC₅₀ values (concentrationinhibiting control activity by 50%) were then determined by nonlinearregression analysis of the inhibition curves. Results are summarized inTable 6, below.

TABLE 6 hSERT hNET hDAT Comp. No. (IC₅₀ nM) (IC₅₀ nM) (IC₅₀ nM) 1 +++++++ ++ 2 ++ ++ ++ 3 + + ++ 4 − − +++ 5 ++ ++ ++ 6 +++ ++ ++ 7 ++ ++ +++8 ++ ++ ++ 9 +++ + ++ 10 ++++ ++ ++ 11 ++++ +++ +++ 12 ++++ ++++ ++ 13++ ++ ++ 14 +++ ++ ++ 15 ++ ++ ++ 16 +++ +++ +++ 17 +++ +++ ++ 18 ++++++ ++ 19 +++ ++ +++ 20 +++ ++ +++ 21 +++ +++ ++ 22 +++ +++ +++ 23 ++++++ +++ 24 ++++ ++++ +++ 25 +++ ++ +++ 26 ++ +++ +++ 27 +++ +++ ++ 28 +++++ ++ 29 +++ +++ ++ 30 ++ ++ ++ 31 ++ ++ ++ ++++ (IC₅₀ < 1 nM); +++(IC₅₀ < 10 nM); ++ (IC₅₀ ≦ 100 nM); + (100 nM < IC₅₀ ≦ 500 nM); −(IC₅₀ > 500 nM)

2.1. Serotonin Functional Uptake Assay for Rat Reuptake Transporter

Quantification of 5-HT uptake was performed using synaptosomes isolatedin a 0.32M sucrose buffer from a male Wistar rat cortex. The uptake ofradiolabelled 5-HT by synaptosomes (100 μg of proteins/point) wasallowed by incubating them in a well for 15 min at 37° C. in presence oftest compounds and [³H]5-hydroxytryptamine (serotonin; 0.1 μCi/point).

Synaptosomes and [³H]serotonin were prepared in a Krebs buffer pH 7.4containing 25 mM NaHCO₃, 11 mM glucose and 50 μM ascorbic acid. Thisincubation buffer was oxygenated during 5 minutes before incubation.Basal control was incubated for 15 minutes at 4° C. in order to avoidany uptake. Following this incubation the uptake was stopped byfiltration through a unifilter 96-wells GFB Packard plate washed withKrebs buffer containing 25 mM NaHCO₃ in order to eliminate the free[³H]serotonin. The radioactivity associated to the synaptosomes retainedon the unifilter corresponding to the uptake was then measured with amicroplate scintillation counter (Topcount, Packard) using ascintillation fluid. Nonspecific binding was measured in the presence ofan excess of cold, unlabeled ligand. Specific binding was obtained bysubtracting nonspecific binding from total binding.

The reference compound was imipramine tested at 10 concentrationsranging from 10⁻¹¹ M to 10⁻⁵ M in order to obtain an IC₅₀ value. See,Perovics and Müller, Arzeim. Forsch./Drug Res., 45:1145-1148 (1995).

2.2. Serotonin Functional Uptake Assay for Human Reuptake Transporter

Inhibition of human serotonin reuptake transporter was assayed using therecombinant human serotonin transporter expressed in HEK-293 cells usinga published method (Gu H et al., J. Biol. Chem. 1994, 269 (10):7124-7130). HEK-293 cells expressing human serotonin transporter wereplated before the assay. Test compound and/or vehicle was preincubatedwith cells in modified HEPES buffer pH 7.1 or pH 7.4 for 20 minutes at18 to 25° C. and 65 nM [³H]serotonin was then added for an additionaltimed incubation period (ten to thirty minutes). Cells with internalized[³H]serotonin were washed and the amount of tritium taken into cells iscounted using a liquid scintillation counter to determine [³H]serotoninuptake. Non-specific binding of tritium was measured in a controlreaction containing 10 μM fluoxetine, and was subtracted from the countsfor assays to correct for non-specific binding of tritium. Reduction of[³H]serotonin uptake by 50 percent or more (≧50%) relative to anuninhibited control reaction indicates significant inhibitory activity.Compounds were screened at 10, 1, 0.1, 0.01 and 0.001 μM. The referencecompound for the assay was fluoxetine, for which the IC₅₀ value of 7.1nM was obtained in a typical experiment.

2.3. Dopamine Functional Uptake Assay for Rat Reuptake Transporter

Quantification of dopamine uptake was performed using synaptosomesisolated in a 0.32 M sucrose buffer from a male Wistar rat striatum. Theuptake of radiolabelled dopamine by synaptosomes (20 μg ofproteins/point) was allowed by incubating them for 15 minutes at 37° C.in the presence of test compounds and [³H]-dopamine (0.1 μCi/point). Theexperiment was performed in a deep well.

Synaptosomes and [³H]-dopamine were prepared in a Krebs buffer pH 7.4containing 25 mM NaHCO₃, 11 mM glucose and 50 μM ascorbic acid. Thisincubation buffer was oxygenated for 5 minutes before incubation. Basalcontrol was incubated for 15 minutes at 4° C. in order to avoid anyuptake. Following this incubation, the uptake was stopped by filtrationthrough a unifilter 96-wells GFB Packard plate washed with Krebs buffercontaining 25 mM NaHCO₃ in order to eliminate free [³H]-dopamine. Theradioactivity associated to the synaptosomes retained onto the unifiltercorresponding to the uptake was then measured with a microplatescintillation counter (Topcount, Packard) using a scintillation fluid.

The reference compound was GRB 12909 tested at 8 concentrations rangingfrom 10⁻¹¹ M to 10⁻⁶ M in order to obtain an IC₅₀ value. See, Jankowskyet al., J. Neurochem. 1986, 46:1272-1276).

2.4. Dopamine Functional Uptake Assay for Human Reuptake Transporter

Inhibition of human dopamine reuptake transporter was assayed using therecombinant human dopamine transporter expressed in either CHO-K1 orHEK293 cells using a published method (Pristupa, Z. B. et al., Mol.Pharmacol. 45: 125-135, 1994). Either CHO-K1 or HEK293 cells expressinghuman recombinant dopamine transporter were plated before the assay.Test compound and/or vehicle was preincubated with cells in modifiedHEPES buffer pH 7.1 or pH 7.4 for 20 minutes at 18 to 25° C. and 50 nM[³H]dopamine was then added for an additional timed incubation period(10 to 30 minutes). After washing the cells to remove [³H]dopamine notinternalized, the cells were lysed, and the amount of tritium in thelysate was measured using a liquid scintillation counter to determine[³H]dopamine uptake. Non-specific binding of tritium was measured in acontrol reaction containing 10 μM nomifensine, and was subtracted fromthe counts for assays to correct for non-specific binding of tritium.Reduction of [³H]dopamine uptake by 50 percent or more (50%) relative toan uninhibited control reaction indicates significant inhibitoryactivity. Compounds were screened at 10, 1, 0.1, 0.01 and 0.001 μM. Thereference compound for the assay was nomifensine, for which the IC₅₀value of 11 nM was obtained in a typical experiment.

2.5. Norepinephrine Functional Uptake Assay for Rat Reuptake Transporter

Quantification of norepinephrine uptake was performed using synaptosomesisolated in a 0.32 M sucrose buffer from a male Wistar rat hypothalamus.The uptake of radiolabelled norepinephrine by synaptosomes (100 μg ofproteins/point) was allowed by incubating them for 20 minutes at 37° C.in presence of test compounds and [³H]-norepinephrine (0.1 μCi/point).The experiment was performed in a deep well.

Synaptosomes and [³H]-norepinephrine were prepared in a Krebs buffer pH7.4 containing 25 mM NaHCO₃, 11 mM glucose and 50 μM ascorbic acid. Thisincubation buffer was oxygenated for 5 minutes before incubation. Basalcontrol was incubated for 20 minutes at 4° C. in order to avoid anyuptake. Following this incubation, the uptake was stopped by filtrationthrough a unifilter 96-wells GFB Packard plate washed with Krebs buffercontaining 25 mM NaHCO₃ in order to eliminate the free[³H]-norepinephrine. The radioactivity associated to the synaptosomesretained onto the unifilter corresponding to the uptake was thenmeasured with a microplate scintillation counter (Topcount, Packard)using a scintillation fluid.

The reference compound was protriptyline tested at 13 concentrationsranging from 10⁻¹¹ M to 10⁻⁵ M in order to obtain an IC₅₀ value. See,Perovics and Müller, Arzeim. Forsch./Drug Res., 45:1145-1148 (1995).

2.6. Norepinephrine Functional Uptake Assay for Human ReuptakeTransporter

Inhibition of human norepinephrine reuptake transporter was assayedusing the recombinant human norepinephrine transporter expressed ineither HEK293 or MDCK cells using a published method (Galli A et al., J.Exp. Biol. 198: 2197-2212, 1995). The cells were plated before theassay. Test compound and/or vehicle was preincubated with cells inmodified HEPES buffer pH 7.1 or pH 7.4 for 20 minutes at 18 to 25° C.Following the preincubation, 25 nM [³H]norepinephrine was added for anadditional timed incubation period (10 to 20 minutes). After the cellswere washed to remove [³H]norepinephrine not internalized, the cellswere lysed, and the amount of tritium in the cell lysate was measuredusing a liquid scintillation counter to determine [³H]norepinephrineuptake. Non-specific binding of tritium was measured in a controlreaction containing 10 μM imipramine (or 10 μM nisoxetine), and wassubtracted from the counts for assays to correct for non-specificbinding of tritium. Reduction of [³H]norepinephrine uptake by 50 percentor more (50%) relative to an uninhibited control reaction indicatessignificant inhibitory activity. Compounds were screened at 10, 1, 0.1,0.01 and 0.001 μM. The reference compounds for the assay weredesipramine and nisoxetine, for which IC₅₀ values of 1.9 nM and 5.3 nMrespectively were obtained in typical experiments.

In Table 6, compound numbers correspond to those used in the Examplesabove. In addition, the following abbreviations have been used in Table6: SERT (serotonin transporter), NET (norepinephrine transporter) andDAT (dopamine transporter).

The above results indicate that compounds of the invention exhibitpotent inhibition of neuronal uptake of NE, DA, and/or 5-HT, and comparefavorably with potencies seen for various existing therapeutic agents.For example, reported potencies (IC₅₀ or K_(i) values) of approved andlaunched drugs include: fluoxetine (PROZAC®), 7 nM for inhibition ofhuman 5-HT reuptake transporter; methylphenidate (RITALIN®), 193 nM and38 nM for inhibition of human dopamine and norepinephrine reuptaketransporters, respectively (Eshleman et al., J. Pharmacol. Exp. Ther.1999, 289: 877-885); amitriptyline (ELAVIL®), 63 nM and 67 nM forinhibition of the human norepinephrine and serotonin reuptaketransporters, respectively and venlafaxine (EFFEXOR®, a so-calledserotonin norepinephrine reuptake inhibitor (SNRI) 145 and 1420 nM, forinhibition of the human serotonin, and norepinephrine reuptaketransporters respectively (Vaishnavi et al., Biol. Psychiatry. 2004, 55:320-322). The multiple inhibition of the neuronal uptake of NE, DAand/or 5-HT displayed by the compounds of the invention provides theclinician with the ability to more effectively treat CNS disorders,including without limitation affective disorders, cerebral functiondisorders, anxiety disorders, neuropathic pain, and migraine or migraineheadache, by elevating various monoamine levels in the brainsimultaneously and over the same dose-range without the need to titrateseparate drugs.

Example 3 Ex Vivo Binding Assays

Receptor occupancy of central noradrenaline (NA), 5-HT and dopamine (DA)transporter sites following peripheral administration of compounds wasdetermined using [³H] nisoxetine, [³H] citalopram and [³H] WIN 35428binding, respectively. Liquid scintillation counting was used toquantify the radioactivity.

3.1. Methods

C57BL/6 mice (25-30 g) were dosed orally with either vehicle or compoundat 4 dose levels. Mice were sacrificed 60 minutes after treatment. Wholebrains were removed and cortex and striata dissected out before beingfrozen on dry ice. The brain tissue was stored at −20° C. until the dayof the assay. The cortex from each hemisphere was frozen separately. Onewas used to determine occupancy of NA transporter sites and the otheroccupancy of 5-HT transporter sites. Striatum was used to determineoccupancy of DA transporter sites.

3.2. Membrane Preparation

Frontal cortex from each hemisphere or striata was homogenisedindividually in ice-cold assay buffer using a tight fitting glass/Teflonhomogeniser and used immediately in the binding assay.

[³H] Citalopram Binding to 5-HT Transporter (SERT) Sites in Mouse Brain

Cortical membranes (400 μl; equivalent to 1.25 mg wet weight oftissue/tube) were incubated with 50 μl of [³H] citalopram at a singleconcentration of 1.3 nM and either 50 μL of buffer (total binding) or 50μL of paroxetine (0.5 μM; non-specific binding) for 1 h at 27° C. Foreach animal, three tubes were used for the determination of totalbinding and three tubes were used for the determination of non-specificbinding.

[³H] Nisoxetine Binding to Norepinephrine Transporter (NET) Sites inMouse Brain

Cortical membranes (400 μl; equivalent to 6.0 mg wet weight oftissue/tube) were incubated with 50 μl of [³H] nisoxetine at a singleconcentration of 0.6 nM and either 50 μl of buffer (total binding) or 50μl of mazindol (1 μM; non-specific binding) for 4 h at 4° C. For eachanimal, three tubes were used for the determination of total binding andthree tubes were used for the determination of non-specific binding.

[³H] WIN 35428 Binding to DA Transporter (DAT) Sites in Mouse Brain

Striatal membranes (200 μl; equivalent to 2 mg wet weight oftissue/tube) were incubated with 25 μl of [³H] WIN 35428 at a singleconcentration of 24 nM and either 25 μl of buffer (total binding) or 25μL of GBR12935 (1 μM; non-specific binding) for 2 h at 4° C. For eachanimal, two tubes were used for the determination of total binding andtwo tubes for the determination of non-specific binding.

Membrane bound radioactivity was recovered by filtration under vacuumthrough Skatron 11731 filters, presoaked in 0.5% PEI, using a Skatroncell harvester. Filters were rapidly washed with ice-cold phosphatebuffer and radioactivity (dpm) was determined by liquid scintillationcounting (1 ml Packard MV Gold scintillator).

3.3. Data Analysis

A value for specific binding (dpm) was generated by the subtraction ofmean non-specific binding (dpm) from mean total binding (dpm) for eachanimal. Data are presented as mean specific binding (dpm) and as apercentage of the vehicle-treated control taken as 100%.

3.4. Results Summary

Ex vivo SERT, NET and DAT binding/receptor occupancy data were generatedfor selected compounds of the invention. Results showed that thecompounds exhibited varying SERT, NET and DAT inhibition ratios.

Example 4 In Vivo Analyses 4.1. Rat Forced Swim Test

The method, which detects antidepressant activity, followed thatdescribed by Porsolt et al (Eur. J. Pharmacol., 47, 379-391, 1978) andmodified by Lucki et al. (Psychopharm., 121, 66-72, 1995). Rats forcedto swim in a situation from which they cannot escape rapidly becomeimmobile. Antidepressants decrease the duration of immobility. Inaddition, distinct patterns of active behaviors are produced byantidepressants that selectively inhibit norepinephrine (NE) andserotonin (5-HT) uptake in this test. Selective NE reuptake inhibitorsdecrease immobility by increasing climbing behaviors whereas selective5-HT reuptake inhibitors decrease immobility by increasing swimmingbehaviors.

Rats were individually placed in a cylinder (Height=40 cm; Diameter=20cm) containing 22 cm water (25° C.) for 15 minutes on the first day ofthe experiment (Session 1) and were then put back in the water 24 hourslater for a 5 minute test (Session 2). The sessions were videotaped andduration of immobility as well as swimming and climbing behaviors duringthe 5 minute test were measured. Twelve rats were tested in each group.The test was performed blind. Compounds were typically evaluated at 3doses (1-30 mg/kg), administered orally 2 times: 24 hours and 30-60minutes before the test (Session 2), and compared with a vehicle controlgroup. Desipramine (20 mg/kg i.p.), administered under the sameexperimental conditions, was used as the positive reference substance.

Data were analyzed by one way analysis of variance (ANOVA) followed bypost-hoc comparisons where appropriate. An effect will be consideredsignificant if p<0.05. Data are represented as the mean and standarderror to the mean (s.e.m). Tested compounds exhibitedantidepressant-like effects with MED's in the range of 10-30 mg/kg, PO.The decrease in immobility produced by these compounds appeared to bedue to increases in swimming and climbing behaviors indicative of mixedtransporter activity (i.e., SNRI profiles).

4.2. Mouse Tail Suspension Test

The method, which detects antidepressant activity, follows thatdescribed by Stem et al (Psychopharmacology, 85, 367-370, 1985).Rodents, suspended by the tail, rapidly become immobile. Antidepressantsdecrease the duration of immobility.

The behavior of the animal was recorded automatically for 5 minutesusing a computerized device (Med-Associates Inc.) similar to thatdeveloped by Steru et al (Prog. Neuropsychopharmacol. Exp. Psychiatry,11, 659-671, 1987). Ten to twelve mice were tested in each group. Thetest was performed blind. Compounds were typically evaluated at 3 doses(1-30 mg/kg), administered orally one time: 30-60 minutes before thetest, and compared with a vehicle control group. Desipramine (100mg/kg), administered under the same experimental conditions, was used asthe positive reference substance.

Data were analyzed by one way analysis of variance (ANOVA) followed bypost-hoc comparisons where appropriate. An effect was consideredsignificant if p<0.05. Data are represented as the mean and standarderror to the mean (s.e.m). Results showed that tested compoundsexhibited an antidepressant-like profile (i.e., significantly decreasedimmobility time) with MED's in the range of 3-30 mg/kg, PO.

4.3. Locomotor Activity

In order to ensure effects of the compounds on immobility time were notrelated to a general stimulant effect on baseline motor activity,locomotor activity was assessed using photocell monitored cages(Med-Associates Inc.). Each test chamber was equipped with infraredphotocell beams to measure movement of the animals. Horizontal andvertical activity were measured

Rats or mice were pretreated with vehicle or test compounds and placedback in home cage, following which they will be individually placed inlocomotor cages and activity was monitored in 5 minute intervals for upto 60 min.

Data were analyzed by one way analysis of variance (ANOVA) followed bypost-hoc comparisons where appropriate. An effect was consideredsignificant if p<0.05. Data are represented as the mean and standarderror to the mean (s.e.m). At doses active in the tail suspension test,no change or a decrease in baseline motor activity was observedindicating that antidepressant-like activity was not due to a generalstimulant effect.

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodiments thatare functionally equivalent are within the scope of this invention.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in theart and are intended to fall within the scope of the appended claims.

1-30. (canceled)
 31. A compound having the formula:

or a pharmaceutically acceptable salt, solvate, enantiomer,diastereomer, racemic mixture, enantiomerically enriched mixture, orenantiomerically pure form thereof, wherein: R¹ is selected from H andC₁-C₃ alkyl; R² and R^(2a) are each independently selected from H andOR³; R³ is independently selected from H and C₁-C₃ alkyl; Ar is selectedfrom phenyl optionally substituted with at least one halogen andunsubstituted naphthyl; X is selected from —CH₂—, —CH₂CH₂—, andCH₂ZCH₂—; Z is selected from and

and O; R⁴ and R⁵ are independently selected from H and OR⁶; and R⁶ isselected from H and C₁-C₃ alkyl.
 32. The compound of claim 31 or apharmaceutically acceptable salt, solvate, enantiomer, diastereomer,racemic mixture, enantiomerically enriched mixture, or enantiomericallypure form thereof, wherein Ar is phenyl substituted with at least onechloro.
 33. The compound of claim 31 or a pharmaceutically acceptablesalt, solvate enantiomer, diastereomer, racemic mixture,enantiomerically enriched mixture, or enantiomerically pure formthereof, wherein Ar has a formula selected from:

wherein X¹ and X² are independently selected from H and halogen, withthe proviso that at least one of X¹ and X² is halogen.
 34. The compoundaccording to claim 33 or a pharmaceutically acceptable salt, solvateenantiomer, diastereomer, racemic mixture, enantiomerically enrichedmixture, or enantiomerically pure form thereof, wherein each of X¹ andX² is independently halogen.
 35. The compound according to claim 34 or apharmaceutically acceptable salt, solvate enantiomer, diastereomer,racemic mixture, enantiomerically enriched mixture, or enantiomericallypure form thereof, wherein each of X¹ and X² is Cl.
 36. The compound ofclaim 31 or a pharmaceutically acceptable salt, solvate, enantiomer,diastereomer, racemic mixture, enantiomerically enriched mixture, orenantiomerically pure form thereof, wherein:

has a formula selected from:


37. The compound of claim 31 or a pharmaceutically acceptable salt orsolvate thereof, wherein:

has a formula selected from:


38. The compound of claim 37 or a pharmaceutically acceptable salt orsolvate thereof, wherein Ar is selected from:


39. The compound of claim 31 or a pharmaceutically acceptable salt orsolvate thereof, wherein:

has the form

and Ar has a formula selected from:


40. The compound of claim 39 or a pharmaceutically acceptable salt orsolvate thereof, wherein the compound has the formula:


41. The compound of claim 39 or a pharmaceutically acceptable salt orsolvate thereof, wherein the compound has the formula:


42. A pharmaceutical composition comprising a compound of claim 31, or apharmaceutically acceptable salt, solvate enantiomer, diastereomer,racemic mixture, enantiomerically enriched mixture, or enantiomericallypure form thereof, and a pharmaceutically acceptable carrier.
 43. Amethod of inhibiting the activity of at least one monoamine transporter,the method comprising contacting the monoamine transporter and acompound of claim 31, or a pharmaceutically acceptable or apharmaceutically acceptable salt, solvate enantiomer, diastereomer,racemic mixture, enantiomerically enriched mixture, or enantiomericallypure form thereof, wherein the monoamine transporter is a serotonintransporter (SERT), a dopamine transporter (DAT), a norepinephrinetransporter (NET), or a combination thereof.
 44. The method of claim 43,wherein the compound of claim 1, or a pharmaceutically acceptable salt,solvate enantiomer, diastereomer, racemic mixture, enantiomericallyenriched mixture, or enantiomerically pure form thereof, inhibits theactivity of at least two different monoamine transporters.
 45. A methodof treating a central nervous system disorder in a patient, the methodcomprising administering to the patient a therapeutically effectiveamount of a compound of claim 31, or a pharmaceutically acceptable salt,solvate enantiomer, diastereomer, racemic mixture, enantiomericallyenriched mixture, or enantiomerically pure form thereof, wherein thecentral nervous system disorder is depression, cognitive deficit,fibromyalgia, pain, sleep disorder, attention deficit disorder (ADD),attention deficit hyperactivity disorder (ADHD), restless leg syndrome,schizophrenia, anxiety, obsessive compulsive disorder, posttraumaticstress disorder, premenstrual dysphoria, or a neurodegenerative disease.46. The method of claim 45, wherein the central nervous system disorderis depression.
 47. The method of claim 46, wherein the depression isselected from major depressive disorder (MDI)), unipolar depression,bipolar disorder, seasonal affective disorder (SAD) and dysthymia. 48.The method of claim 45, wherein the neurodegenerative disease isParkinson's disease.
 49. The method of claim 45, wherein the sleepdisorder is sleep apnea.
 50. The method of claim 45, wherein the pain isneuropathic pain.